JP6831324B2 - Certain protein kinase inhibitors - Google Patents

Description

[Cross-reference of related applications]
The present application claims the priority of US Provisional Application No. 62/073993. The provisional application is incorporated herein by reference in its entirety.

Certain compounds and / or pharmaceutically acceptable salts thereof that can inhibit the kinase activity of PI3K and can be useful in the treatment of inflammatory and autoimmune disorders and hyperproliferative disorders such as cancer. Is provided.

[background]
Phosphoinositide 3-kinases (PI3K) belong to a large family of lipid signaling kinases that play important roles in cellular processes. The cellular process involves cell proliferation, differentiation, migration, and apoptosis. The PI3K family is divided into three classes, I, II, and III, based on sequence homology and lipid substrate specificity. Among these, class I PI3K includes PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ and is the most studied.

Class I PI3K is a heterodimer formed by two subunits, a catalytic subunit (p110) and a regulatory subunit (p85). The catalytic subunit p110 has four isotypes, α, β, γ, and δ. p110α has a role in insulin-dependent signaling, p110β has a role in platelet aggregation, thrombosis, and insulin signaling, and p110γ and p110δ are expressed primarily in leukocytes and lymphocyte activation, It has a role in mast cell degranulation and chemical migration. The catalytic p110 subunit associates with the p85 regulatory subunit. Based on the reception of the upstream activation signal, the p85 regulatory subunit releases its inhibition of p110. As a result, p110 interacts with the lipid membrane to phosphorylate phosphatidylinositol-4,5-bisphosphate (PIP2) at the 3'-OH position of the inositol ring, resulting in phosphatidylinositol-3,4,5. -Triphosphati (PIP3) can be produced. PIP3 then activates downstream signals, resulting in abnormal regulation of metabolism and protein synthesis and cell growth, proliferation, and survival.

All four Class I catalytic PI3K isoforms exhibit a characteristic expression pattern in vivo. p110α and p110β are universally expressed in mammalian tissues. On the other hand, p110γ and p110δ are considered to be more selectively expressed in leukocytes, endothelial cells, and smooth muscle cells. Defects in p110α or p110β induce embryonic lethality. Although p110γ-deficient mice develop and reproduce normally, these mice have a suboptimal immune response. This is due to defects in T cell activation and neutrophil and macrophage migration. P110δ-deficient mice are also able to grow and reproduce, but show significant defects in T and B cell activation.

The PI3K pathway is generally deregulated in cancer cells. Expression of PI3Kδ is generally limited to hematopoietic cell types. The p110δ isoform is constitutively activated in B cell tumors, the inactivation of which has demonstrated its important role in the treatment of B cell malignancies. PI3Kδ has been shown to play an important role in the signaling pathways of various types of leukemia. Therefore, PI3Kδ has become an attractive target for drug treatment. Preclinical data in acute myeloid leukemia and chronic lymphocytic leukemia have identified PI3Kδ as a predominant isoform in these diseases. Therefore, compounds with inhibitory activity against PI3K may be useful in the prevention and treatment of cancer.

In addition to cancer, PI3K has also been suggested as a target for inflammatory and autoimmune disorders.

PI3K inhibitors have been disclosed in the art, for example, in International Publication No. 2012146666, No. 2003035075, and US Patent Application Publication No. 2011015212, but many have short half-life or toxicity issues. .. Therefore, as an alternative for the treatment of hyperproliferative disorders, there is a need for novel PI3K inhibitors that have at least one favorable property selected from efficacy, stability, selectivity, toxicity, and pharmacokinetic properties. Sexual selection exists. In this regard, a novel class of PI3K inhibitors is provided herein.

In the present specification, specific novel 6-6 or 6-5 member condensed pyridone ring derivatives and pharmaceutical compositions thereof, and their use as pharmaceuticals are disclosed.

［式中、
Ａ−Ｂは、６−６又は６−５員の縮合ピリドン環系であり、同環系は、好ましくは、

から選択され、
Ｗは、アリール及びヘテロアリールから選択され、そしてここで、アリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^１は、水素、ハロゲン、シアノ、Ｃ_１〜１０アルキル（例えば、Ｃ_１〜６アルキル）、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル（例えば、Ｃ_３〜６シクロアルキル）、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてここで、アリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^２は、水素、Ｃ_１〜１０アルキル（例えば、Ｃ_１〜６アルキル）、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル（例えば、Ｃ_３〜６シクロアルキル）、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてアリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^３は、水素、Ｃ_１〜１０アルキル、及びＣ_３〜１０シクロアルキルから選択され、そしてここで、アルキル及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^４は、水素、ハロゲン、シアノ、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、及びＣ_３〜１０シクロアルキル−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^５は、それぞれ独立して、水素、Ｃ_１〜１０アルキル（例えば、Ｃ_１〜６アルキル）、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ＯＲ^８、ＮＲ^７Ｓ（Ｏ）_ｒＲ^８、ＮＯ_２、ハロゲン、Ｓ（Ｏ）_ｒＲ^７、ＳＲ^８、Ｓ（Ｏ）_２ＯＲ^７、ＯＳ（Ｏ）_２Ｒ^８、Ｓ（Ｏ）_ｒＮＲ^７Ｒ^８、ＮＲ^７Ｒ^８、Ｏ（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）Ｒ^７、ＣＯ_２Ｒ^８、ＣＯ_２（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、ＯＣ（Ｏ）Ｒ^７、ＣＮ、Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）Ｒ^８、ＯＣ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）ＯＲ^８、ＮＲ^７Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＣＲ^７（Ｎ−ＯＲ^８）、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２、及びＯＣＦ_３から選択され、そしてここで、アルキル、アルケニル、アルキニル、及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^６ａは、それぞれ独立して、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ＯＲ^８、ＮＲ^７Ｓ（Ｏ）_ｒＲ^８、ＮＯ_２、ハロゲン、Ｓ（Ｏ）_ｒＲ^７、ＳＲ^８、Ｓ（Ｏ）_２ＯＲ^７、ＯＳ（Ｏ）_２Ｒ^８、Ｓ（Ｏ）_ｒＮＲ^７Ｒ^８、ＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＯＲ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＳＲ^８、（ＣＲ^９Ｒ^１０）_ｔＳ（Ｏ）_ｒＲ^８、（ＣＲ^９Ｒ^１０）_ｔＣＯ_２Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＣＯ_２Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＯＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＳＯ_２ＮＲ^７Ｒ^８、Ｏ（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）Ｒ^７、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＯＲ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＳＲ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＳ（Ｏ）_ｒＲ^８、ＣＯ_２Ｒ^８、ＣＯ_２（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、ＯＣ（Ｏ）Ｒ^７、ＣＮ、Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）Ｒ^８、ＯＣ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）ＯＲ^８、ＮＲ^７Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＣＲ^７（Ｎ−ＯＲ^８）、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２、及びＯＣＦ_３から選択され、
Ｒ^６ｂは、それぞれ独立して、Ｒ^６ａ、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、
各Ｒ^７及び各Ｒ^８は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、シクロアルキル、シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから独立して選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてアリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、又は
Ｒ^７及びＲ^８は、それらが付着している原子と共に、４〜１２員の複素環を形成しており、同複素環は、酸素、硫黄、及び窒素から独立して選択される、０、１、又は２個の更なるヘテロ原子を含有し、かつ１又は２個のＲ^６ｂ基で場合により置換されており、
各Ｒ^９及び各Ｒ^１０は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、シクロアルキル、シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから独立して選択され、又は
Ｒ^９及びＲ^１０は、それらが付着している炭素原子と共に、３〜７員の環を形成しており、同環は、酸素、硫黄、及び窒素から独立して選択される、０、１、又は２個のヘテロ原子を含有し、かつ１又は２個のＲ^６ａ基で場合により置換されており、
ｍは、０、１、２、３、及び４から独立して選択され、
各ｒは、１及び２から独立して選択され、
各ｔは、１、２、及び３から独立して選択される］
で表示される化合物及び／又はその薬学的に許容し得る塩が開示される。 In one aspect, as used herein, formula (I):

[During the ceremony,
AB is a 6-6 or 6-5 member condensed pyridone ring system, preferably the ring system.

Selected from
W is selected from aryl and heteroaryl, where each aryl and heteroaryl are unsubstituted or independently selected from R ^6b at least one substituent, eg, 1, 2, ... Substituted with 3 or 4 substituents,
R ¹ is hydrogen, halogen, cyano, C _1-10 alkyl (eg C _1-6 alkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl (eg C _3-6). Cycloalkyl), C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl Selected, and where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or independently selected from R ^6a , at least one substituent, such as 1, 2, 3 , Or, where the aryl and heteroaryl are substituted, respectively, or at least one substituent selected independently of R ^6b , eg, 1, 2 Substituted with 3, or 4 substituents,
R ² is hydrogen, C _1-10 alkyl (eg C _1-6 alkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl (eg C _3-6 cycloalkyl), Selected from C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, and Here, alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted or at least one substituent independently selected from R ^6a , such as 1, 2, 3, or four. Substituents substituted with substituents, and aryls and heteroaryls, respectively, are unsubstituted or at least one substituent independently selected from R ^6b , eg, 1, 2, 3 or 4 substituents. Substituted with a group
R ³ is selected from hydrogen, C _1-10 alkyl, and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted, respectively, or are selected independently of R ^6a. Substituted with at least one substituent, eg, 1, 2, 3, or 4 substituents.
R ⁴ is selected from hydrogen, halogen, _{cyano, C 1 to 10 alkyl, C 2 to 10 alkenyl, C 2 to 10 alkynyl, C 3 to 10} cycloalkyl, and _{C 3 to 10} cycloalkyl _{-C 1 to 4} alkyl And here, alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or at least one substituent independently selected from R ^6a , such as 1, 2, 3, or 4 Substituted with one substituent
R ⁵ are independently hydrogen, C _1-10 alkyl (eg, C _1-6 alkyl), C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cyclo. Alkyne-C _1-4 Alkyne, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , Halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰⁾ ) _T CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ selected from, where alkyl, alkenyl, alkynyl, and cyclo Each alkyl is unsubstituted or substituted with at least one substituent selected independently of R ^6a , such as 1, 2, 3 or 4 substituents.
R ^6a are independently C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , respectively. NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C ( O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ) , CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃
R ^6b is independently selected from R ^6a , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl.
Each R ⁷ and each R ⁸ contains hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, Aryl-C _1-4 Alk, Heteroaryl, and Heteroaryl-C _1-4 Alk, respectively, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are unsubstituted. Or is substituted with at least one substituent selected independently of R ^6a , such as 1, 2, 3, or 4 substituents, and aryl and heteroaryl are unsubstituted, respectively. Yes, or substituted with at least one substituent selected independently of R ^6b , such as 1, 2, 3, or 4 substituents, or R ⁷ and R ⁸ have them attached. It forms a 4- to 12-membered heteroatom with the atoms, which form 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, and nitrogen. Containing and optionally substituted with 1 or 2 R ^6b groups
Each R ⁹ and each R ¹⁰ are hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, or R ⁹ and R ¹⁰ are 3 to 3 with the carbon atom to which they are attached. It forms a 7-membered ring, which contains 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and 1 or 2 R ^6a. In some cases substituted with groups,
m is independently selected from 0, 1, 2, 3, and 4
Each r is independently selected from 1 and 2
Each t is selected independently of 1, 2, and 3]
The compounds labeled in and / or pharmaceutically acceptable salts thereof are disclosed.

In another aspect, a pharmaceutical composition comprising a compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient is disclosed.

In yet another embodiment, a method for modulating PI3K, in a therapeutically effective amount of a compound represented by formula (I) and / or pharmaceutically thereof for a system or subject in need thereof. Disclosed are methods comprising administering an acceptable salt or pharmaceutical composition thereof.

In yet another embodiment, a method of treating, alleviating, or preventing a condition in response to inhibition of PI3K, which is represented by an effective amount of formula (I) for a system or subject in need of such treatment. Disclosed is a method comprising treating the condition by administering the compound and / or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, optionally in combination with a second therapeutic agent. Will be done.

Alternatively, the use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a condition mediated by PI3K is disclosed. In certain embodiments, the compounds of the present disclosure can be used alone or in combination with a second therapeutic agent to treat a condition mediated by PI3K.

Alternatively, a compound represented by formula (I) for treating a condition mediated by PI3K is disclosed.

Specifically, the conditions herein include, but are not limited to, autoimmune diseases, transplantation diseases, infectious diseases, or cell proliferation disorders.

Further, a method for treating a cell proliferative disorder that is pharmaceutically acceptable to a system or subject in need of such treatment in an effective amount of the compound represented by formula (I) and / or its pharmaceutically acceptable. Disclosed are methods that include treating the condition by administering the resulting salt or pharmaceutical composition thereof, optionally in combination with a second therapeutic agent.

Alternatively, the use of a compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a cell growth disorder is disclosed. In certain examples, the compounds of the present disclosure can be used alone or in combination with chemotherapeutic agents to treat cell proliferative disorders.

Specifically, the cell proliferative disorders disclosed herein are lymphomas, osteosarcomas, melanomas, or tumors of the breast, kidney, prostate, colonic rectal, thyroid, ovary, pancreas, nerves, lungs, uterus or Including, but not limited to, gastrointestinal tumors.

In the above method for using the compounds of the present disclosure, the compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof shall be administered to a system containing cells or tissues, or to a subject. Can be done. The subject includes a mammalian subject, such as a human or animal subject.

Specific Terminology Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs. All patents, patent applications and publications referenced throughout the disclosure of this specification are incorporated by reference in their entirety, unless otherwise noted. If there are multiple definitions of terms herein, the definitions in this section will prevail. Such identifiers are subject to change if URLs or other such identifiers or addresses are referred to, and certain information on the Internet may change, but equivalent information. Is understood to be found by searching the internet or other suitable sources. References to it demonstrate the availability and public dissemination of such information.

It should be understood that the general description above and the detailed description below are merely exemplary and descriptive and do not limit the claimed subject matter in any way. In the present application, the use of the singular form includes the plural form unless otherwise specified. As used herein and in the appended claims, the singular forms "a", "an", and "the" shall include multiple referents unless expressly stated otherwise in the context. Please note. It should also be noted that the use of "or" means "and / or" unless otherwise noted. Furthermore, the use of the term "inclusion" and other forms, such as "include", "includes", and "included", is not limiting. .. Similarly, the use of the term "comprising" and other forms, such as "comprise", "comprises", and "comprised", is not limited. Absent.

Definitions of standard chemical terms can be found in the references. The reference material includes Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Unless otherwise noted, mass spectrometry, NMR, HPLC, IR, and UV / Vis spectroscopy, as well as conventional methods of pharmacology, within the scope of those skilled in the art are utilized. Unless a specific definition is provided, the technical terms used in analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry described herein, as well as analytical chemistry, synthetic organic chemistry, and medical and pharmaceutical chemistry studies. Technical terms used with respect to laboratory techniques and techniques are well known in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, formulation, and delivery, as well as patient treatment. Reaction and purification techniques can be performed, for example, using kits specified by the manufacturer, or as commonly achieved in the art or as described herein. The techniques and techniques described above are generally conventional methods well known in the art, as well as those described in various general and more specific references cited and discussed throughout this specification. It can be performed. Throughout the specification, the groups and substituents can be selected by one of ordinary skill in the art to provide stable moieties and compounds.

If the substituents are specified by their customary chemical formulas listed from left to right, they equally include chemically identical substituents that would result from describing the structure from right to left. .. As a non-limiting example, CH ₂ O is equivalent to OCH ₂ .

The term "alkyl" refers to both branched and linear saturated aliphatic hydrocarbon groups with a specified number of carbon atoms. Unless otherwise noted, "alkyl" refers to C _1- C ₆ alkyl. For example, C _{1 to} C ₆ include a group having 1, 2, 3, 4, 5, or 6 carbons in a linear or branched arrangement, as in "C _{1 to 6} alkyl". Is defined as. For example, "C _1-8 alkyl" includes, but is limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, i-butyl, pentyl, hexyl, heptyl, and octyl. Not done.

The term "cycloalkyl" means a saturated aliphatic cyclic hydrocarbon group having a specific number of carbon atoms. Unless otherwise noted, "cycloalkyl" refers to C _3-10 cycloalkyl. For example, "cycloalkyl" includes, but is not limited to, cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, and cyclohexyl.

The term "alkenyl" refers to a linear, branched, or cyclic non-aromatic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon double bond. In some embodiments, there is one carbon-carbon double bond. Up to four non-aromatic carbon-carbon double bonds can be present. Therefore, "C _2-6 alkenyl" means an alkenyl group having 2 to 6 carbon atoms. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methylbutenyl, and cyclohexenyl. The linear, branched, or cyclic moieties of the alkenyl group can contain a double bond and can be substituted if a substituted alkenyl group is indicated.

The term "alkynyl" refers to a linear, branched, or cyclic hydrocarbon group containing 2-10 carbon atoms and at least one carbon-carbon triple bond. In some embodiments, up to three carbon-carbon triple bonds can be present. Therefore, "C _2-6 alkynyl" means an alkynyl group having 2 to 6 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and 3-methylbutynyl. The linear, branched, or cyclic moieties of the alkynyl group can contain triple bonds and can be substituted if a substituted alkynyl group is indicated.

The term "halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine.

The term "aryl" refers to 5- and 6-membered carbocyclic aromatic rings, such as benzene; bicyclic ring systems in which at least one ring is a carbocyclic ring and an aromatic ring, such as naphthalene, indan, and 1. , 2,3,4-tetrahydroquinoline; and includes tricyclic ring systems in which at least one ring is a carbocycle and an aromatic ring, such as fluorene. When the aryl substituent is bicyclic or tricyclic and at least one ring is a non-aromatic ring, the attachment is understood to be mediated by an aromatic ring.

For example, aryl is a 5- and 6-membered carbocyclic aromatic ring condensed into a 5- to 7-membered heterocycle containing one or more heteroatoms selected from N, O, and S. including. However, the attachment point is on the condition that it is in the carbocyclic aromatic ring. A divalent group formed from a substituted benzene derivative and having a free valence at the ring atom is called a substituted phenylene group. The divalent group obtained from a monovalent polycyclic hydrocarbon group has a name ending in "-yl" by removing one hydrogen atom from a carbon atom having a free valence. It is called by adding "iden" to the name of the corresponding monovalent group. For example, a naphthyl group having two attachment points is called naphthalidene. However, aryl does not include any heteroaryl, as defined separately below, or does not overlap with heteroaryl at all. Therefore, when one or more carbocyclic aromatic rings are fused with a heterocyclic aromatic ring, the resulting ring system is heteroaryl, not the aryl defined herein.

The term "heteroaryl"
One or more selected from N, O, and S, for example 1 to 4, or in some embodiments, containing 1 to 3 heteroatoms, the remaining ring atoms being carbon 5 ~ 8-membered aromatic monocyclic ring,
One or more selected from N, O, and S, for example 1-4, or in some embodiments, containing 1-3 heteroatoms, the remaining ring atoms being carbon, at least An 8- to 12-membered bicyclic ring in which one heteroatom is present in the aromatic ring, and one or more selected from N, O, and S, such as 1-4, or some embodiments. Refers to a 11-14-membered tricyclic ring containing 1 to 3 heteroatoms, the remaining ring atom being carbon, and at least one heteroatom present in the aromatic ring.

If the total number of S and O atoms in the heteroaryl group exceeds 1, the heteroatoms are not adjacent to each other. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle does not exceed one.

Examples of heteroaryl groups are 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl (counting priority 1 from the assigned binding position). , 3,5-pyrimidinyl, 1-pyrazolyl, 2,3-pyrazolyl, 2,4-imidazolinyl, isooxazolyl, oxazolyl, thiazolyl, thiadiazolyl, tetrazolyl, thienyl, benzothienyl, frill, benzofuryl, benzoimidazolinyl, indolinyl, pyrididinyl , Triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinoline, but not limited to these.

Further heteroaryl groups include, but are not limited to, pyrrolyl, isothiazolyl, triazinyl, pyrazinyl, pyridadinyl, indolyl, benzotriazolyl, quinoxalinyl, and isoquinolinyl. Similar to the definition of heterocycle below, "heteroaryl" is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.

A divalent group obtained from a monovalent heteroaryl group ending in "yl" by removing one hydrogen atom from an atom having a free valence is the corresponding monovalent group. It is called by adding "Iden" to the name. For example, a pyridyl group with two attachment points is pyridylidene. Heteroaryls do not include or overlap with the aryls defined above.

If the heteroaryl substituent is bicyclic or tricyclic and at least one ring is a non-aromatic ring or does not contain a heteroatom, the attachment is via an aromatic ring or contains a heteroatom. It is understood to be each through a ring.

In the present disclosure, the term 6-6 or 5-6 membered fused ring system refers to two 6-membered aryls or heteroaryls fused to each other, or 5-membered aryls or heteroaryls 6-. It is used to indicate that it is condensed with a member aryl or heteroaryl. For example, in a 6-6 or 5-6 member condensed pyridone ring system, the 6-membered aryl or heteroaryl is fused with the pyridone ring, or the 5-membered aryl or heteroaryl is fused with the pyridone ring. Refers to that.

The term "heterocycle" (and variations thereof, such as "heterocyclic" or "heterocyclyl") usually has 3-12 ring atoms and at least 2 carbon atoms. And additionally contains a combination comprising one or more, preferably 1-3 heteroatoms, independently selected from oxygen, sulfur, and nitrogen, and at least one of the aforementioned heteroatoms. Widely refers to a single alicyclic ring. Alternatively, the heterocycle defined above can be a polycyclic ring system (eg, bicyclic), in which two or more rings are fused or crosslinked with each other, or , Can be a spiro. And here, at least one such ring contains one or more heteroatoms that are independently selected from oxygen, sulfur, and nitrogen. Also, the "heterocycle" contains one or more heteroatoms selected from N, O, and S and is fused with 5- and 6-membered carbocyclic aromatic rings, 5-7-. It also refers to the member heterocycle. However, the attachment point is on the heterocycle. The ring may be saturated or may have one or more double bonds (ie, it may be partially unsaturated). The heterocycle can be replaced by oxo. The attachment point can be a carbon or heteroatom in the heterocycle. However, the condition is that the adhesion results in the formation of a stable structure. It is understood that if the heterocycle has a substituent, the substituent can be attached to any atom in the ring, regardless of whether it is a heteroatom or a carbon atom. However, the condition is that a stable chemical structure is provided. Heterocycles do not overlap with heteroaryls.

を含むが、これらに限定されない。 Suitable heterocycles are 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3- (counting priority 1 from the assigned binding position). Includes, but is not limited to, piperidinyl, 4-piperidinyl, and 2,5-piperazinyl. It is also assumed that the morpholinyl group contains 2-morpholinyl and 3-morpholinyl (when oxygen is assigned to priority 1 and counted). The substituted heterocycles are ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-. Also includes 1-thiomorpholinyl. Bicyclic heterocycles

Including, but not limited to.

As used herein, "arylalkyl" refers to an alkyl moiety substituted with an aryl group. Examples of arylalkyl groups include benzyl, phenethyl, and naphthylmethyl groups. In some embodiments, the arylalkyl group has 7-20 or 7-11 carbon atoms. When used in the expression "aryl C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of that portion and does not describe the number of atoms in the aryl portion of that portion. Similarly, when used in the expression "aryl C _1-10 alkyl", the term "C _1-10 " refers to the alkyl portion of that portion and does not describe the number of atoms in the aryl portion of that portion. Absent.

As used herein, "heterocyclyl alkyl" refers to an alkyl substituted with heterocyclyl. When used in the expression "heterocyclyl-C _1-6 alkyl", the term "C _1-6 " refers to the alkyl portion of that portion and does not describe the number of atoms in the heterocyclyl moiety of that portion.

As used herein, "cycloalkylalkyl" refers to an alkyl substituted with cycloalkyl. When used in the expression "C _3-10 cycloalkylalkyl", the term " _C3-10 " refers to the cycloalkyl portion of that portion and does not describe the number of atoms in the alkyl portion of that portion. .. When used in the expression "C _{3 to 7} cycloalkylalkyl", the term "C _{3 to 7"} refers to a cycloalkyl portion of the moiety and does not describe the number of atoms in the alkyl portion of the moiety .. When used in the expression "C _3-8 cycloalkylalkyl", the term " _C3-8 " refers to the cycloalkyl portion of that portion and does not describe the number of atoms in the alkyl portion of that portion. .. When used in the expression "cycloalkyl C _1-10 alkyl", the term "C _1-10 " refers to the alkyl portion of that portion and does not describe the number of atoms in the cycloalkyl portion of that portion. ..

As used herein, "heteroarylalkyl" refers to an alkyl substituted with a heteroaryl. When used in the expression "heteroaryl C _1-4 alkyl", the term "C _1-4 " refers to the alkyl portion of that portion and does not describe the number of atoms in the heteroaryl portion of that portion. .. Similarly, when used in the expression "heteroaryl C _1-10 alkyl", the term "C _1-10 " means the alkyl portion of that portion and describes the number of atoms in the heteroaryl portion of that portion. It's not something to do.

For the avoidance of doubt, for example, references to substitutions of alkyl, cycloalkyl, heterocyclyl, aryl, and / or heteroaryl refer to the substitution of each of these groups individually and to the substitution of a combination of these groups. That is, when R ¹ is an arylalkyl, the aryl moiety may be unsubstituted or at least one substituent selected independently of R ^6b , eg, 1, 2, 3, or 4 It may be substituted with a substituent. The alkyl moiety may also be unsubstituted or substituted with at least one substituent, for example 1, 2, 3 or 4 substituents, which are selected independently of R ^6a .

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids. Salts obtained from inorganic bases can be selected from, for example, salts of aluminum, ammonium, calcium, copper, iron II, iron I, lithium, magnesium, manganese II, manganese I manganese, potassium, sodium, and zinc. Can be done. Further, for example, pharmaceutically acceptable salts obtained from inorganic bases can be selected from salts of ammonium, calcium, magnesium, potassium, and sodium. The solid salt can be present in one or more crystal structures and can also be present in the form of a hydrate. Salts obtained from pharmaceutically acceptable organic non-toxic bases include, for example, primary, secondary, and tertiary amines, substituted amines (including natural substituted amines), cyclic amines, and basic ion exchange resins. For example, arginine, betaine, caffeine, choline, N, N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholin, N-ethylpiperidine. , Glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, prokine, purine, theobromine, triethylamine, trimethylamine, and tripropylamine, tromethamine salts. it can.

If the compounds disclosed herein are basic, salts can be prepared using pharmaceutically acceptable non-toxic acids selected from inorganic and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid. , Apple acid, mandelic acid, methanesulfonic acid, mucinic acid, nitrate, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid. In some embodiments, such acids can be selected from, for example, citric acid, hydrobromic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid, fumaric acid, and tartaric acid.

The term "protecting group" or "Pg" refers to a substituent that can be commonly used to block or protect a particular functionality while reacting with other functional groups on the compound. .. For example, an "amine protecting group" is a substituent that adheres to an amino group that blocks or protects amine functionality in a compound. Suitable amino protecting groups include, but are not limited to, acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to a substituent of a hydroxy group that blocks or protects hydroxy functionality. Suitable protecting groups include, but are not limited to, acetyl and silyl. "Carboxy protecting group" refers to a substituent of a carboxy group that blocks or protects carboxy functionality. Common carboxy protecting groups are --CH ₂ CH ₂ SO ₂ Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-). Includes nitrophenylsulphenyl) ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. See TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991 for a general description of protecting groups and their use.

The term "administration" of a compound and / or a pharmaceutically acceptable salt and or "administration" of the compound and / or a pharmaceutically acceptable salt is a compound and / or pharmaceutically acceptable thereof. It should be understood to mean providing salt to individuals with a recognized need for treatment.

The term "effective amount" will elicit the biological or medical response of tissues, systems, animals, or humans sought by researchers, veterinarians, doctors of medicine, or other clinicians, compounds and / Or it means a pharmaceutically acceptable amount of salt.

As used herein, the term "composition" refers to a product that contains a particular component in a particular amount, as well as any product that results directly or indirectly from a combination of a particular component in a particular amount. Is intended to include. Such terms for pharmaceutical compositions are derived from products containing the active ingredient and the inert ingredients that make up the carrier, as well as combinations, complexations, or aggregations of any two or more ingredients, or 1 It is intended to include any product that results directly or indirectly from the dissociation of one or more components or from other types of reactions or interactions of one or more components.

The term "pharmaceutically acceptable" means compatible with the other ingredients of the formulation and not unacceptably harmful to its recipient.

As used herein, in reference to an individual suffering from a disorder, condition, etc., the term "subject" includes mammals and non-mammals. Examples of mammals are mammal classes of any member: humans, non-human primates such as chimpanzees and other apes and monkey species; domestic animals such as cows, horses, sheep, goats, pigs; domestic animals such as rabbits. , Dogs, and cats; including, but not limited to, rodents, such as laboratory animals including rats, mice, and guinea pigs. Examples of non-mammals include, but are not limited to, birds, fish and the like. In one embodiment of the methods and compositions provided herein, the mammal is a human.

As used herein, the terms "treat," "treat," or "treat," as well as other grammatical equivalents, alleviate, relieve, or ameliorate a disease or condition. To prevent the symptoms, improve or prevent the underlying metabolic cause of the symptoms, inhibit the disease or condition, eg, stop the onset of the disease or condition, relieve the disease or condition, relieve the disease or condition It is intended to include prevention, including reversing, relieving the condition caused by the disease or condition, or stopping the signs of the disease or condition. The term further includes achieving therapeutic and / or prophylactic benefits. Therapeutic benefit means eradication or amelioration of the underlying disorder being treated. Therapeutic benefits are also achieved by eradicating or ameliorating one or more physiological signs associated with the underlying disorder. This allows improvement to be observed in the patient, even though the patient may still be suffering from the underlying disorder. For prophylactic benefits, the composition reports one or more physiological signs of the disease to patients at risk of developing a particular disease, or even if the disease has not been diagnosed. Can be administered to patients who are ill.

［式中、
Ａ−Ｂは、６−６又は６−５員の縮合ピリドン環系であり、同環系は、

から選択され、
Ｗは、アリール及びヘテロアリールから選択され、そしてここで、アリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^１は、水素、ハロゲン、シアノ、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてここで、アリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^２は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてアリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^３は、水素、Ｃ_１〜１０アルキル、及びＣ_３〜１０シクロアルキルから選択され、そしてここで、アルキル及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^４は、水素、ハロゲン、シアノ、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、及びＣ_３〜１０シクロアルキル−Ｃ_１〜４アルキルから選択され、そしてここで、アルキル、アルケニル、アルキニル、及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^５は、それぞれ独立して、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ＯＲ^８、ＮＲ^７Ｓ（Ｏ）_ｒＲ^８、ＮＯ_２、ハロゲン、Ｓ（Ｏ）_ｒＲ^７、ＳＲ^８、Ｓ（Ｏ）_２ＯＲ^７、ＯＳ（Ｏ）_２Ｒ^８、Ｓ（Ｏ）_ｒＮＲ^７Ｒ^８、ＮＲ^７Ｒ^８、Ｏ（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）Ｒ^７、ＣＯ_２Ｒ^８、ＣＯ_２（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、ＯＣ（Ｏ）Ｒ^７、ＣＮ、Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）Ｒ^８、ＯＣ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）ＯＲ^８、ＮＲ^７Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＣＲ^７（Ｎ−ＯＲ^８）、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２、及びＯＣＦ_３から選択され、そしてここで、アルキル、アルケニル、アルキニル、及びシクロアルキルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、
Ｒ^６ａは、それぞれ独立して、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、Ｃ_３〜１０シクロアルキル、Ｃ_３〜１０シクロアルキル−Ｃ_１〜４アルキル、ＯＲ^８、ＮＲ^７Ｓ（Ｏ）_ｒＲ^８、ＮＯ_２、ハロゲン、Ｓ（Ｏ）_ｒＲ^７、ＳＲ^８、Ｓ（Ｏ）_２ＯＲ^７、ＯＳ（Ｏ）_２Ｒ^８、Ｓ（Ｏ）_ｒＮＲ^７Ｒ^８、ＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＯＲ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＳＲ^８、（ＣＲ^９Ｒ^１０）_ｔＳ（Ｏ）_ｒＲ^８、（ＣＲ^９Ｒ^１０）_ｔＣＯ_２Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＣＯ_２Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＯＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＣＯＮＲ^７Ｒ^８、（ＣＲ^９Ｒ^１０）_ｔＮＲ^７ＳＯ_２ＮＲ^７Ｒ^８、Ｏ（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）Ｒ^７、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＯＲ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＮＲ^７Ｒ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＳＲ^８、Ｃ（Ｏ）（ＣＲ^９Ｒ^１０）_ｔＳ（Ｏ）_ｒＲ^８、ＣＯ_２Ｒ^８、ＣＯ_２（ＣＲ^９Ｒ^１０）_ｔＣＯＮＲ^７Ｒ^８、ＯＣ（Ｏ）Ｒ^７、ＣＮ、Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）Ｒ^８、ＯＣ（Ｏ）ＮＲ^７Ｒ^８、ＮＲ^７Ｃ（Ｏ）ＯＲ^８、ＮＲ^７Ｃ（Ｏ）ＮＲ^７Ｒ^８、ＣＲ^７（Ｎ−ＯＲ^８）、ＣＨＦ_２、ＣＦ_３、ＯＣＨＦ_２、及びＯＣＦ_３から選択され、
Ｒ^６ｂは、それぞれ独立して、Ｒ^６ａ、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから選択され、
各Ｒ^７及び各Ｒ^８は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、シクロアルキル、シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから独立して選択され、そしてここで、アルキル、アルケニル、アルキニル、シクロアルキル、及びヘテロシクリルはそれぞれ、非置換であり、又は、Ｒ^６ａから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、そしてアリール及びヘテロアリールはそれぞれ、非置換であり、又は、Ｒ^６ｂから独立して選択される少なくとも１つの置換基、例えば、１、２、３、又は４つの置換基で置換されており、又は
Ｒ^７及びＲ^８は、それらが付着している原子と共に、４〜１２員の複素環を形成しており、同複素環は、酸素、硫黄、及び窒素から独立して選択される、０、１、又は２個の更なるヘテロ原子を含有し、かつ１〜２個のＲ^６ｂ基で場合により置換されており、
各Ｒ^９及び各Ｒ^１０は、水素、Ｃ_１〜１０アルキル、Ｃ_２〜１０アルケニル、Ｃ_２〜１０アルキニル、シクロアルキル、シクロアルキル−Ｃ_１〜４アルキル、ヘテロシクリル、ヘテロシクリル−Ｃ_１〜４アルキル、アリール、アリール−Ｃ_１〜４アルキル、ヘテロアリール、及びヘテロアリール−Ｃ_１〜４アルキルから独立して選択され、又は
Ｒ^９及びＲ^１０は、それらが付着している炭素原子と共に、３〜７員の環を形成しており、同環は、酸素、硫黄、及び窒素から独立して選択される、０、１、又は２個のヘテロ原子を含有し、かつ１〜２個のＲ^６ａ基で場合により置換されており、
ｍは、０、１、２、３、及び４から独立して選択され、
各ｒは、１及び２から独立して選択され、
各ｔは、１、２、及び３から独立して選択される］
で表示される化合物及び／又はその薬学的に許容し得る塩。 1. 1. Equation (I):

[During the ceremony,
AB is a 6-6 or 6-5 member condensed pyridone ring system, which is a ring system.

Selected from
W is selected from aryl and heteroaryl, where each aryl and heteroaryl are unsubstituted or independently selected from R ^6b at least one substituent, eg, 1, 2, ... Substituted with 3 or 4 substituents,
R ¹ is hydrogen, halogen, cyano, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl are selected, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are Each is unsubstituted or substituted with at least one substituent selected independently of R ^6a , such as 1, 2, 3, or 4 substituents, and here aryl and hetero. Each aryl is unsubstituted or substituted with at least one substituent, such as 1, 2, 3, or 4 substituents, which are independently selected from R ^6b .
R ² is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C ₁ Selected from _{~ 4alkyl} , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted. Or is substituted with at least one substituent selected independently of R ^6a , such as 1, 2, 3, or 4 substituents, and aryl and heteroaryl are unsubstituted, respectively. Yes, or substituted with at least one substituent selected independently of R ^6b , such as 1, 2, 3, or 4 substituents.
R ³ is selected from hydrogen, C _1-10 alkyl, and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted, respectively, or are selected independently of R ^6a. Substituted with at least one substituent, eg, 1, 2, 3, or 4 substituents.
R ⁴ is selected from hydrogen, halogen, _{cyano, C 1 to 10 alkyl, C 2 to 10 alkenyl, C 2 to 10 alkynyl, C 3 to 10} cycloalkyl, and _{C 3 to 10} cycloalkyl _{-C 1 to 4} alkyl And here, alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or at least one substituent independently selected from R ^6a , such as 1, 2, 3, or 4 Substituted with one substituent
R ⁵ are independently hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC ( O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF _{3 are} selected, where alkyl, alkenyl, alkynyl, and cycloalkyl are unsubstituted, respectively. Alternatively, it is substituted with at least one substituent, for example 1, 2, 3, or 4 substituents, which are independently selected from R ^6a .
R ^6a are independently C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , respectively. NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C ( O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ) , CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃
R ^6b is independently selected from R ^6a , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl.
Each R ⁷ and each R ⁸ contains hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, and where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are respectively unsubstituted. Or is substituted with at least one substituent selected independently of R ^6a , such as 1, 2, 3, or 4 substituents, and aryl and heteroaryl are unsubstituted, respectively. Yes, or substituted with at least one substituent selected independently of R ^6b , such as 1, 2, 3, or 4 substituents, or R ⁷ and R ⁸ have them attached. It forms a 4- to 12-membered heteroatom with the atoms, which form 0, 1, or 2 additional heteroatoms independently selected from oxygen, sulfur, and nitrogen. Containing and optionally substituted with 1-2 R ^6b groups,
Each R ⁹ and each R ¹⁰ are hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, or R ⁹ and R ¹⁰ are 3 to 3 with the carbon atom to which they are attached. It forms a 7-membered ring, which contains 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen, and 1-2 R ^6a. In some cases substituted with groups,
m is independently selected from 0, 1, 2, 3, and 4
Each r is independently selected from 1 and 2
Each t is selected independently of 1, 2, and 3]
Compounds labeled with and / or pharmaceutically acceptable salts thereof.

から選択される、１記載の化合物及び／又はその薬学的に許容し得る塩。 2. 2. AB is

The compound according to 1 and / or a pharmaceutically acceptable salt thereof selected from.

である、２記載の化合物及び／又はその薬学的に許容し得る塩。 3. 3. AB is

2. The compound according to 2 and / or a pharmaceutically acceptable salt thereof.

である、３記載の化合物及び／又はその薬学的に許容し得る塩。 4. AB is

The compound according to 3 and / or a pharmaceutically acceptable salt thereof.

5. R ⁵ is selected from hydrogen, halogen, CF ₃ , C _1-10 alkyl, and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted or independent of R ^6a , respectively. Is substituted with at least one substituent, eg, 1, 2, 3, or 4 substituents, and R ^6a is any one of 1-4, as described in 1. The compound described in the above and / or a pharmaceutically acceptable salt thereof.

6. The compound according to ⁵ , wherein R ⁵ is selected from hydrogen, halogen, methyl, ethyl, CF ₃ , and cyclopropyl, and / or a pharmaceutically acceptable salt thereof.

7. The compound according to 6 and / or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen, chloro, methyl, ethyl, CF ₃ , and cyclopropyl.

8. 7. The compound according to 7 and / or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from chloro, methyl, and CF ₃ .

9. R ¹ is aryl, and where aryl is unsubstituted or at least one substituent independently selected from R ^6b , eg, 1, 2, 3 or 4 substituents. A compound according to any one of 1 to 8 and / or a pharmaceutically acceptable salt thereof, wherein R ^6b is substituted with 1 and as described in 1.

10. R ¹ is phenyl, and where phenyl is unsubstituted or at least one substituent independently selected from R ^6b , such as 1, 2, 3 or 4 substituents. 9. The compound according to 9, wherein R ^6b is a halogen, and / or a pharmaceutically acceptable salt thereof, which is substituted with.

11. Salts R ¹ is phenyl, and wherein phenyl is unsubstituted or, where fluoro is substituted, acceptable 10 compound and / or its pharmaceutically described.

12. R ² is selected from C _1-10 alkyl and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted or at least one substitution selected independently of R ^6a. The compound according to any one of 1 to 11 and / or a pharmacy thereof, which is substituted with a group, for example, 1, 2, 3, or 4 substituents, and R ^6a is as described in 1. Tolerable salt.

13. R ² is methyl, ethyl, isopropyl, and is selected from cyclopropyl, 12 compound and / or the pharmaceutically acceptable salts described.

14. W is heteroaryl, and here heteroaryl is unsubstituted or at least one substituent independently selected from R ^6b , eg, 1, 2, 3 or 4 substitutions. The compound according to any one of 1 to 13 and / or a pharmaceutically acceptable salt thereof, which is substituted with a group.

である、１４記載の化合物及び／又はその薬学的に許容し得る塩。 15. W is

14. The compound according to 14 and / or a pharmaceutically acceptable salt thereof.

16. W is a pyrimidine, and where the pyrimidine is unsubstituted or at least one substituent independently selected from R ^6b , such as 1, 2, 3 or 4 substituents. A compound according to 14 and / or a pharmaceutically acceptable salt thereof, which has been substituted and R ^6b is as described in 1.

である、１６記載の化合物及び／又はその薬学的に許容し得る塩。 17. W is

The compound according to 16 and / or a pharmaceutically acceptable salt thereof.

18. The compound according to any one of 1 to 17, and / or a pharmaceutically acceptable salt thereof, wherein R ³ is hydrogen.

19. R ⁴ is hydrogen, compound and / or the pharmaceutically acceptable salts of any one claim 1 to 18.

20. The following 7- (1-((9H-purin-6-yl) amino) ethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
2- (1-((9H-Prin-6-yl) amino) ethyl) -3-phenyl-4H-quinolizidine-4-one,
2- (1-((9H-Prin-6-yl) amino) propyl) -3-phenyl-4H-quinolizidine-4-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (2-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-ethyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (2-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-Prin-6-yl) amino) ethyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] Pyridine-5 -On,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridine-5 -On,
7-(1-((9H-purin-6-yl) amino) ethyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one ,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridine -5-on,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one ,
2-Amino-4-methyl-6-((1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) pyrimidine-5 -Carbonitrile,
2-Amino-4-((1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) -6 -A compound selected from methylpyrimidine-5-carbonitrile and / or a pharmaceutically acceptable salt thereof.

In another aspect thereof, a pharmaceutical composition comprising the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof is provided.

In yet another embodiment, the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof, an indication of the disease state to which the composition should be administered, storage information about the composition, and the like. A kit is provided that includes dosage information and instructions containing information in one or more forms selected from the group consisting of instructions on how to administer the composition. In one particular variant, the kit comprises compounds of multiple dosage forms.

In yet another embodiment, the product is provided comprising the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof, and a packaging material. In one variant, the packaging material comprises a container for containing the compound. In one particular variant, the container is labeled indicating one or more members of the group consisting of the disease state to which the compound is to be administered, storage information, dose information, and / or instructions on how to administer the compound. including. In another variant, the product contains compounds of multiple dosage forms.

In a further aspect thereof, a therapeutic method is provided that comprises administering to the subject the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof.

In another aspect, a method of inhibiting PI3K kinase is provided, which comprises contacting PI3K with a compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof is present in the subject in order to inhibit PI3K in vivo. A method of inhibiting PI3K is provided.

In a further aspect thereof, a method of inhibiting PI3K comprising administering to a subject a first compound that is converted to a second compound in vivo, wherein the second compound comprises PI3K in vivo. A method is provided that inhibits and the second compound is the compound according to any one of 1-20 and / or a pharmaceutically acceptable salt thereof.

In another aspect, PI3K is a method of treating a disease state in which PI3K has an activity that contributes to the pathology and / or signs of the disease state, the compound according to any one of 1 to 20 and / or the pharmaceutical thereof. Methods are provided that include the presence of an acceptable amount of salt in the subject in a therapeutically effective amount for the disease state.

In a further aspect thereof, a method of treating a disease state in which PI3K has an activity that contributes to the pathology and / or signs of the disease state, the first compound being converted to a second compound in vivo. A method is provided in which a second compound inhibits PI3K in vivo, including administration to a subject. It is noted that the compounds of the present invention can be first or second compounds.

In one variant of each of the above methods, the disease state is a cancerous hyperproliferative disorder (eg, brain, lung, squamous epithelial cells, bladder, gastrointestinal tract, pancreas, breast, head, neck, kidney cells, kidney, ovary, Cancer of the prostate, colonic rectum, epidermis, esophagus, testis, gynecology, or thyroid); non-cancerous hyperproliferative disorders (eg, benign hyperplasia of the skin (eg, psoriasis), re-stenosis, and benign prostate enlargement (BPH) )); Pancreatitis; Renal disease; Pain; Preventing blast cell transplantation; Diseases associated with angiogenesis or angiogenesis (eg, tumor angiogenesis, acute and chronic inflammatory diseases such as rheumatoid arthritis, atherosclerotic arteries) Sclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema, and scleroderma, diabetes, diabetic retinopathy, premature infant retinopathy, age-related yellow spot degeneration, hemangiomas, glioma, melanoma, capsicum sarcoma, And treating cancers of the ovary, breast, lung, pancreas, prostate, colon, and epidermis; asthma; neutrophil migrating (eg, reperfusion injury and inflammatory arthritis in myocardial infarction and attack); Septic shock; T-cell-mediated diseases for which immune suppression may be effective (eg, organ transplant rejection, transplant-to-host disease, erythematosus, multiple sclerosis, and prevention of rheumatoid arthritis); atherosclerosis; growth factors Inhibition of keratinocyte response to cocktails; selected from the group consisting of chronic obstructive pulmonary disease (COPD), as well as other diseases.

In another aspect, a method of treating a disease state is provided in which mutations in the PI3K gene contribute to the pathology and / or signs of the disease state (eg, melanoma, lung cancer, colon cancer, and other tumor types). ..

In yet another aspect, the invention relates to the use of any of the compounds and variations of the above embodiments as a pharmaceutical. In yet another aspect thereof, the present invention relates to the use of the compound according to any one of 1 to 20 and / or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting PI3K.

In a further aspect thereof, the present invention is a compound according to any one of 1 to 20 in the manufacture of a medicament for treating a disease state, wherein PI3K has an activity that contributes to the pathology and / or signs of the disease state. And / or the use of pharmaceutically acceptable salts thereof.

Administration and Pharmaceutical Compositions Generally, the compounds of the present disclosure are either alone or in combination with one or more therapeutic agents by any of the useful and acceptable methods known in the art. In the above, it will be administered in a therapeutically effective amount. The therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compounds used, and other factors known to those of skill in the art. For example, for the treatment of neoplastic diseases and immune system disorders, the dose required will also vary depending on the mode of administration, the particular condition being treated, and the desired effect.

In general, satisfactory results are shown when systemically obtained at daily doses of about 0.001-about 100 mg / kg body weight, or in particular about 0.03-2.5 mg / kg body weight. .. The daily doses shown in larger mammals, eg humans, range from about 0.5 mg to about 2000 mg, or above all, from about 0.5 mg to about 1000 mg, for example in divided doses up to 4 times daily. , Or can be conveniently administered in a delayed form. A unit dosage form suitable for oral administration contains about 1-50 mg of the active ingredient.

The compounds of the present disclosure can be prepared by any conventional route, eg, enteric, eg, orally, eg, in the form of tablets or capsules; parenterally, eg, injectable solutions or suspensions. It can be administered in the form of an agent; or topically, for example, in the form of a lotion, gel, ointment, or cream, or in the form of a nasal or suppository, as a pharmaceutical composition.

A pharmaceutical composition comprising a compound of the present disclosure in the form of a lyophilized or pharmaceutically acceptable salt in combination with at least one pharmaceutically acceptable carrier or diluent is mixed, granulated and coated. It can be produced by a conventional method by a process of thawing or lyophilizing. For example, in a conventional manner, a pharmaceutical composition comprising a compound of the present disclosure in combination with at least one pharmaceutically acceptable carrier or diluent can be mixed with a pharmaceutically acceptable carrier or diluent. Can be manufactured. The unit dosage form for oral administration contains, for example, about 0.1 mg to about 500 mg of active substance.

In one embodiment, the pharmaceutical composition is a liquid preparation of the active ingredient. The solution includes a suspending agent or a dispersant, for example, an isotonic aqueous solution. In the case of lyophilized compositions containing the active ingredient alone or with a carrier such as mannitol, the dispersant or suspending agent can be constructed prior to use. The pharmaceutical compositions can be sterilized and / or adjuvants such as preservatives, stabilizers, wetting agents, or emulsifying agents, solubilizers, salts for regulating osmotic pressure and / Or can contain a buffer. Suitable preservatives include, but are not limited to, antioxidants such as ascorbic acid or fungicides such as sorbic acid or benzoic acid. Liquids or suspensions include thickeners (including, but not limited to, sodium carboxymethyl cellulose, carboxymethyl cellulose, dextran, polyvinylpyrrolidone, gelatin) or solubilizers such as Tween80 (polyoxyethylene (20) sorbitan mono. -Oleart) can be further included.

Suspensions in oils can include, as oil components, habitual, vegetable, synthetic, or semi-synthetic oils for injection purposes. Examples include, as an acid component, a liquid fatty acid ester containing 8 to 22 carbon atoms, or, in some embodiments, a long chain fatty acid having 12 to 22 carbon atoms. Suitable liquid fatty acid esters are lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidonic acid, behenic acid, or corresponding unsaturated acids such as oleic acid, elaidic acid, elca. Contains, but is not limited to, acids, elaidic acid, and linoleic acid, and if desired, antioxidants such as vitamin E, 3-carotene, or 3,5-di-tert-butyl-hydroxytoluene. Can be contained. The alcohol component of these fatty acid esters can have 6 carbon atoms and can be monovalent or multivalent, eg, monovalent, divalent, or trivalent alcohols. Suitable alcohol components include, but are not limited to, methanol, ethanol, propanol, butanol, or pentanol or isomers thereof; glycols, and glycerol.

Other suitable fatty acid esters are ethyl-oleate, isopropylmillistart, isopropyl palmitate, LABRAFIL® M 2375 (polyoxyethylene glycerol), LABRAFIL® M 1944 CS (by alcohol decomposition of apricot oil). Saturated polyglycolylated glycerides prepared and containing glycerides and polyethylene glycol esters), LABRASOL ™ (prepared by alcohol decomposition of TCM and containing glycerides and polyethylene glycol esters; all GaKefosse, France (Obtained from) and / or MIGLYOL® 812 (triglyceride of saturated fatty acids with chain lengths C8 to C12 from Huls AG, Germany), and vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, large Including, but not limited to, bean oil or peanut oil.

The pharmaceutical composition for oral administration is, for example, combining the active ingredient with one or more solid carriers, granulating the resulting mixture as needed, and including the mixture or granules with additional excipients. It can be obtained by further processing to form tablets or tablet cores.

As used herein, a suitable carrier refers to a relatively non-toxic compound or agent that facilitates the uptake of the compound into cells or tissues. The carrier comprises fillers such as sugars such as lactose, saccharose, mannitol or sorbitol, cellulose preparations and / or calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate and binders such as binders such as. It also contains starches such as corn, wheat, or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone, and / or, if desired, disintegrants such as the starches, carboxys described above. Includes, but is not limited to, methyl starch, crosslinked polyvinylpyrrolidone, alginic acid or salts thereof, such as sodium alginate. Further excipients include lubricants and lubricants such as silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate and / or polyethylene glycol or derivatives thereof.

The tablet core can include, among other things, concentrated sugar solutions (which can include gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide), or coating solutions in suitable organic solvents or solvent mixtures, or intestines. Appropriate, and optionally enteric, coatings can be provided by the use of coating solutions for the preparation of soluble coatings, solutions of suitable cellulose preparations, such as acetyl cellulose phthalate or hydroxypropyl methyl cellulose phthalate. Dyes or pigments can be added to tablets or tablet coatings, for example for specific purposes or to indicate different doses of the active ingredient.

Pharmaceutical compositions for oral administration can also include hard capsules containing gelatin or soft sealed capsules containing gelatin and plasticizers such as glycerol or sorbitol. Hard capsules contain the active ingredient in the form of granules, eg, mixed with a filler, eg, corn starch, a binder, and / or a lubricant, eg, talc or magnesium stearate, and optionally a stabilizer. can do. In soft capsules, the active ingredient may be dissolved or suspended in a suitable liquid excipient such as fatty oil, paraffin oil, or liquid polyethylene glycol, or fatty acid ester of ethylene or propylene glycol. it can. Stabilizers and, for example, polyoxyethylene sorbitan fatty acid ester-type surfactants can also be added to the soft capsules.

A pharmaceutical composition suitable for rectal administration is, for example, a suppository containing a combination of an active ingredient and a suppository substrate. Suitable suppository substrates are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycol, or higher alkanols.

Pharmaceutical compositions suitable for parenteral administration contain water-soluble forms, such as aqueous solutions of the active ingredient of water-soluble salts, or thickeners, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran. Aqueous injection suspensions containing stabilizers can optionally be included. Optionally, the active ingredient with the excipient can also be in the form of a lyophilized product and can be made into a liquid by the addition of a suitable solvent prior to parenteral administration. For example, the liquid preparation used for parenteral administration can also be used as an infusion liquid preparation. The preparation for injection is usually carried out under sterile conditions, for example by filling in an ampoule or vial and sealing the container.

The compounds of the present disclosure can be administered as a single active ingredient or with other agents useful for neoplastic diseases or for immunomodulation dosing regimens. For example, the compounds of the present disclosure are pharmaceutical compositions effective for the various diseases described above, such as cyclophosphamide, 5-fluorouracil, fludalabine, gemcitabine, cisplatin, carboplatin, vincristin, vinblastin, etopocid, irinotecan, paclitaxel, In combination with docetaxel, lyxan, doxorbicin, gefinitib, or imatinib; or cyclosporin, rapamycin, ascomycin, or their immune suppression analogs, such as cyclosporin A, cyclosporin G, FK-506, sirolimus, or everolimus, corti Costeroids such as prednison, cyclophosphamide, azathioprene, methotrexate, gold salt, sulfasalazine, antimalaria, brechinal, leflunomide, misolibin, mycophenolic acid, mycophenorate, mofetil, 15-deoxysperguarin, immune suppression Monoclonal antibodies such as leukocyte receptors such as MHC, CD2, CD3, CD4, CD7, CD25, CD28, I CD40, CD45, CD58, CD80, CD86, CD152, CD137, CD154, ICOS, LFA-1, VLA-4. Alternatively, it can be used in combination with monoclonal antibodies to those ligands, or other immunomodulation compounds, such as CTLA 41g, based on the present disclosure.

The disclosure includes a) a first agonist of the compounds of the present disclosure disclosed herein in free or pharmaceutically acceptable salt form, and b) at least one agonist. Pharmaceutical combinations, such as kits, are also provided. The kit can include instructions for its administration.

Various methods can be developed to synthesize the compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof. Representative methods for synthesizing the compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof are provided in Examples. However, the compound represented by the formula (I) and / or a pharmaceutically acceptable salt thereof can also be synthesized by other synthetic routes that can be created by others.

It will be readily recognized that the particular compound represented by formula (I) has an atom that binds to another atom that imparts a particular stereochemistry (eg, a chiral center) to the compound. .. The synthesis of the compound represented by formula (I) and / or a pharmaceutically acceptable salt thereof can result in the formation of mixtures of various stereoisomers (enantiomers, diastereomers). Unless a particular stereochemistry is specified, the compound enumeration is intended to include all of the various possible stereoisomers.

The compound represented by the formula (I) can also be prepared as a pharmaceutically acceptable acid addition salt, for example, by reacting a free base compound with a pharmaceutically acceptable inorganic or organic acid. it can. Alternatively, the pharmaceutically acceptable base addition salt of the compound represented by the formula (I) can be prepared, for example, by reacting a free acid type compound with a pharmaceutically acceptable inorganic or organic base. it can. Inorganic and organic acids and bases suitable for the preparation of pharmaceutically acceptable salts of the compounds represented by formula (I) are described in the definition section of the present application. Alternatively, the salt type compound represented by formula (I) can be prepared using a salt of the starting material or an intermediate.

The compound represented by the free acid type or the free base type formula (I) can be prepared from the corresponding base addition salt or acid addition salt type. For example, the acid addition salt type compound represented by the formula (I) can be converted to the corresponding free base by treating with an appropriate base (for example, ammonium hydroxide solution, sodium hydroxide, etc.). it can. The compound represented by the base addition salt type formula (I) can be converted to the corresponding free acid by treatment with, for example, an appropriate acid (for example, hydrochloric acid or the like).

The N-oxide of the compound represented by the formula (I) and / or a pharmaceutically acceptable salt thereof can be prepared by a method known to those skilled in the art. For example, N-oxide oxidizes the non-oxidizing compound represented by formula (I) in a suitable inert organic solvent (eg, halogenated hydrocarbon, eg dichloromethane) at about 0-80 ° C. It can be prepared by treatment with an agent (eg, trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid, meta-chloroperoxybenzoic acid, etc.). Alternatively, the N-oxide of the compound represented by formula (I) can be prepared from the appropriate starting material N-oxide.

The non-oxidizing compound represented by the formula (I) is derived from the N-oxide of the compound represented by the formula (I), for example, in a suitable inert organic solvent (eg, acetonitrile, ethanol, aqueous dioxane, etc.). Can be prepared by treating with a reducing agent (for example, sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, phosphorus tribromide, etc.) at 0 to 80 ° C. ..

The protected derivative of the compound represented by the formula (I) can be produced by a method known to those skilled in the art. A detailed description of the techniques applicable to the formation and removal of protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

As used herein, the symbols and conventions used in these processes, schemes, and examples are used in current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. Matches the one. Standard one-letter or three-letter abbreviations are commonly used to specify amino acid residues. The amino acid residue is assumed to be in the L configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial sources and used without further purification. For example, the following abbreviations can be used in the examples and throughout the specification. g (grams); mg (milligrams); L (liters); mL (milliliters); μL (microliters); psi (pounds per square inch); M (moles); mM (mmols); i. v. (Intravenous); Hz (hertz); MHz (megahertz); mol (mol); mmol (mmol); RT (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatograph) Graphics); Rt (retention time); RP (reverse phase); MeOH (methanol); i-PrOH (isopropanol); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (anhydrous trifluoroacetic acid); THF (tetratransferase) ); DMSO (dimethylsulfoxide); EtOAc (ethyl acetate); DME (1,2-dimethoxyethane); DCM (methanol); DCE (dichloroethane); DMF (N, N-dimethylformamide); DMPU (N, N'-Dimethylpropyleneurea); CDI (1,1-carbonyldiimidazole); IBCF (isobutylchloroformate); HOAc (acetate); HOSu (N-hydroxysuccinimide); HOBT (1-hydroxybenzotriazole); Et ₂ O (Diethyl ether); EDCI (1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride); BOC (tert-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexylcarbodiimide) CBZ (benzyloxycarbonyl); Ac (acetyl); atm (pressure); TMSE (2- (trimethylsilyl) ethyl); TMS (trimethylsilyl); TIPS (triisopropylsilyl); TBS (t-butyldimethylsilyl); DMAP (4-Dimethylaminopyridine); MeOH (methyl); MeOH (methoxy); Et (ethyl); tBu (tert-butyl); HPLC (fast liquid chromatography); BOP (bis (2-oxo-3-oxazolidinyl)) Phosphinate chloride); TBAF (tetra-n-butylammonium fluoride); m-CPBA (meth-chloroperbenzoic acid).

References to ether or Et ₂ O are for diethyl ether. Brine refers to a saturated aqueous solution of NaCl. Unless otherwise noted, all temperatures are expressed in degrees Celsius. All reactions were performed at RT in an inert atmosphere unless otherwise noted.

^{1 1} H NMR spectra were recorded on Varian Mercury Plus 400. Chemical shifts are expressed in parts per million (ppm). The coupling constant is a unit of hertz (Hz). The split pattern describes the apparent multiplicity and is designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br (broad).

Shimadzu LC / MS single with low resolution mass spectrum (MS) and compound purity data, equipped with electrospray ionization (ESI) sources, UV detectors (220 and 254 nm), and evaporative light scattering detector (ELSD). Obtained in a quadrupole system. Thin layer chromatography was performed on a 0.25 mm Superchemgroup silica gel plate (60F-254) and visualized with UV light, 5% ethanolic phosphomolybdic acid, ninhydrin, or p-anisaldehyde solution. Flash column chromatography was performed on silica gel (200-300 mesh, Branch of Qingdao Haiyang Chemical Co., Ltd).

Synthesis Schemes The compounds represented by formula I or II and / or pharmaceutically acceptable salts thereof can be synthesized according to various reaction schemes. Some exemplary schemes are provided below and in the Examples. Other reaction schemes can be readily conceived by those skilled in the art in light of the present disclosure.

In the reactions described herein below, reactive functional groups such as hydroxy, amino, imino, thio, or carboxy groups, which avoid their undesired involvement in the reaction in the final product. If desired, it may need to be protected. Traditional protecting groups can be used according to standard practice. See, for example, T.W. Greene and P. G. M. Wuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991.

Synthetic methods for preparing the compounds of the present disclosure are exemplified in the schemes and examples below. Starting materials are commercially available or can be prepared according to procedures known in the art or exemplified herein.

The intermediates shown in the schemes below are either known in the literature or can be prepared by a variety of methods known to those of skill in the art.

As shown in Scheme 1, the compounds represented by Formula I can be synthesized from amine II and aryl halides or heteroaryl III. These can be prepared by various methods known in the literature or known to those skilled in the art. A compound represented by formula I by coupling amine II with a halide III in the presence of a base such as DIPEA or in a solvent such as IPA or under other coupling conditions known in the literature. Is provided.

One synthetic pathway for II is shown in Scheme 2, as exemplified in the preparation of Intermediate II. Preparation starts with II-a. II-a is commercially available or can be synthesized according to procedures known in the literature. The Witich reaction of II-a with a Hoener reagent such as II-b in the presence of a base such as NaH provides the diester II-c. Heating II-c with an acid such as polyphosphoric acid results in pyridone II-d. Halogenation of II-d with a reagent such as NBS or NIS, followed by a metal-catalyzed coupling reaction, such as Suzuki coupling, gives II-f. The ester II-f, or by DIBAL-H reduction, or by either by a series of NaBH ₄ / CaCl ₂ reduction and MnO ₂ oxidation can be converted into the aldehyde II-h. Addition of Grignard to aldehyde II-f provides alcohol II-i. The hydroxyl group of II-i can be converted to an amine group to give Intermediate II as shown in Scheme I. By reacting the hydroxy group of II-i with a reagent such as MsCl or TosCl, it can be converted into a leaving group to give II-j. Substitution of the leaving group in II-j with a nucleophile, eg, amine or azide, results in Intermediate II or Azide II-k, respectively. Reducing agents, for example, by reduction of the azide II-k by Ph ₃ P, it gives the intermediates II. Azide II-k can also be obtained by the mitsunobo reaction of alcohol II-i with DPPA.

The chiral division approach for obtaining Enantiomerically Pure Intermediate II is outlined in Scheme 3. Coupling of amine II with pure enantiomerically pure O-methylmandelic acid gives a diastereomeric mixture of II-j. The mixture can be separated by either column or recrystallization. Cleavage of the amide bond at II-j yields an enantiomerically pure intermediate II-R or II-S.

Alternatively, an enantiomerically pure intermediate II-R or II-S can be synthesized by the procedure shown in Scheme 4. Imine II-n is provided by condensation of aldehyde II-h with (R) or (S) -tert-butanesulfinamide in a solvent such as DCM in the presence of a base such as Cs ₂ CO _3. .. Addition of Grignard to imine II-n gives II-p. II-p can be converted to an enantiomerically pure intermediate II-R or II-S by treatment with aqueous HCl.

In some cases, the order in which the reaction schemes described above are carried out can be changed to facilitate the reaction or avoid unwanted reaction products. The following examples are provided so that the present invention can be better understood. These examples are merely exemplary and should not be construed as limiting the invention.

４−メチルチアゾール−２−カルバルデヒド（１ａ）
４−メチルチアゾール−２−カルバルデヒド（１ａ）を、国際公開公報第２０１１１３８７５１号に記載された方法に従って調製した。 Example 1
7- (1- (9H-purine-6-ylamino) ethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1)

4-Methylthiazole-2-carbaldehyde (1a)
4-Methylthiazole-2-carbaldehyde (1a) was prepared according to the method described in WO 2011138751.

Dimethyl 2- (diethoxyphosphoyl) succinate (1b)
Dimethyl 2- (diethoxyphosphoryl) succinate (1b) was prepared according to the method described in Eur. J. Med. Chem. 2010, 45: 4403.

Dimethyl 2-((4-methylthiazole-2-yl) methylene) succinate (1c)
NaH (60%, 0.092 g, 2.4 mmol) was added to a solution of dimethyl 2- (diethoxyphosphoryl) succinate (1b) (0.56 g, 2.0 mmol) in THF (10 mL) at 0 ° C. , The mixture was stirred at 0-5 ° C. for 1 hour. A solution of 4-methylthiazole-2-carbaldehyde (1a) (0.25 g, 2.0 mmol) in THF (2 mL) was added. The mixture was r. t. Was stirred for 3 hours. The reaction was quenched with saturated aqueous _NH 4 Cl (20 mL), and extracted with EtOAc (2 × 30mL). The extract was washed with saturated brine (30 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel flash column chromatography eluting with PE / EtOAc (10: 1) to give the notation compound dimethyl 2-((4-methylthiazole-2-yl) methylene) succinate (1c). .. MS-ESI (m / z): 256 [M + 1] ⁺ .

Methyl 3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-carboxylate (1d)
A mixture of dimethyl 2-((4-methylthiazole-2-yl) methylene) succinate (1c) (3.77 g, 14.7 mmol) and PPA (50.0 g) was stirred at 80 ° C. overnight. The reaction mixture was poured onto 250 g of ice and adjusted to pH = 9-10 with Na ₂ CO ₃ . The mixture was extracted with DCM (3 x 100 mL). The extract was washed with saturated brine (100 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10: 1-2: 1) and the notation compound methyl 3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine. -7-carboxylate (1d) was given. MS-ESI (m / z): 225 [M + 1] ⁺ .

Methyl 6-iodo-3-methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carboxylate (1e)
NIS (0) in a solution of methyl 3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-carboxylate (1d) (1.5 g, 6.7 mmol) in DCM (50 mL). .9 g, 4 mmol) was added. The mixture was r. t. Was stirred for 3 hours. A further portion of NIS (0.9 g, 4 mmol) was added to r. t. The mixture was stirred for 3 hours, and the last portion of NIS (0.2 g, 0.88 mmol) was added. The mixture was r. t. Stir for an additional hour with, dilute with DCM (50 mL), wash with saturated Na ₂ S ₂ O ₃ aqueous solution (50 mL), saturated NaHCO ₃ aqueous solution (50 mL), and saturated brine (50 mL) and with Na ₂ SO ₄ . It was dried. After filtration and evaporation, the residue is purified by silica gel column chromatography eluting with PE / EtOAc (10: 1-5: 1) and the notation compound methyl 6-iodo-3-methyl-5-oxo- 5H-thiazolo [3,2-a] pyridine-7-carboxylate (1e) was given. MS-ESI (m / z): 350 [M + 1] ⁺ .

Methyl 3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-carboxylate (1f)
Methyl 6-iodo-3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-carboxylate (1e) (0.17 g, 0.5 mmol) in dioxane (6 mL), commercially available A mixture of phenylboronic acid (0.12 g, 1.0 mmol) and Cs ₂ CO ₃ (0.65 g, 2.0 mmol) was degassed and Pd (PPh ₃ ) ₂ Cl ₂ (0.07 g, 0.1 mmol). ) Was added and degassed again. The mixture at 85 ° C., and stirred for 5 hours under _{N 2} atmosphere. The mixture was r. t. It was cooled to and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (10: 1-4: 1) and the notation compound methyl 3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2]. -A] Pyridine-7-carboxylate (1f) was given. MS-ESI (m / z): 300 [M + 1] ⁺ .

3-Methyl-5-oxo-6-Phenyl-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (1 g)
In a solution of methyl 3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-carboxylate (1f) (0.36 g, 1.2 mmol) in DCM (15 mL) , DIBAl-H (4 mL, 6 mmol) was added at −78 ° C. The mixture was stirred at −78 to −60 ° C. for 0.5 hours and the reaction was stopped at −78 ° C. with MeOH (5 mL). A 15% aqueous NaOH solution was added and r. t. Was stirred for 0.5 hours. The mixture was extracted with DCM (2 x 50 mL) and the extract was washed with brine (50 mL) and dried over Na ₂ SO ₄ . After filtration and evaporation, the residue is purified by silica gel column chromatography eluting with PE / EtOAc (10: 1-2: 1) and the notation compound 3-methyl-5-oxo-6-phenyl-5H- Thiazolo [3,2-a] pyridine-7-carbaldehyde (1 g) was given. MS-ESI (m / z): 270 [M + 1] ⁺ .

7- (1-Hydroxyethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (1h)
In a solution of 3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-carbaldehyde (1 g) (0.15 g, 0.6 mmol) in THF (10 mL). MeMgBr (0.8 mL, 2.4 mmol) was added at −78 ° C. The mixture was r. t. Warm slowly to r. t. Was stirred for 1 hour. The reaction with saturated aqueous _NH 4 Cl (15 mL), quenched with 0 ° C., and extracted with EtOAc (2 × 50mL). The extract was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and evaporated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (2: 1) and labeled compound 7- (1-hydroxyethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2]. -A] Pyridine-5-one (1h) was given. MS-ESI (m / z): 286 [M + 1] ⁺ .

1- (3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl methanesulfonate (1i)
7- (1-Hydroxyethyl) -3-methyl-6-Phenyl-5H-thiazolo [3,2-a] pyridin-5-one (1h) (0.065 g, 0.23 mmol) in DCM (5 mL) TEA (0.101 g, 1 mmol) was added to the solution of (1) at 0 ° C., followed by MsCl (0.06 g, 0.5 mmol). The mixture was r. t. The reaction was stopped at 0 ° C. with water (20 mL). The mixture was extracted with DCM (25 mL), washed with brine (15 mL) and dried over Na ₂ SO ₄ . It is filtered and evaporated to give the crude product of 1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl methanesulfonate (1i). Gave. The crude product was used directly in the next step. MS-ESI (m / z): 364 [M + 1] ⁺ .

7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1j)
1- (3-Methyl-5-oxo-6-Phenyl-5H-thiazolo [3,2-a] Pyridine-7-yl) ethyl methanesulfonate (1i) (0.075 g, 0) in IPA (5 mL) NH ₃ was bubbled to a solution of .2 mmol) at 0 ° C. for 0.5 hours and the mixture was stirred in a sealed tube at 70 ° C. overnight. Concentrate and purify the crude product by silica gel column chromatography eluting with DCM / MeOH (20: 1) to the notation compound 7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [ 3,2-a] Pyridine-5-one (1j) was given. MS-ESI (m / z): 285 [M + 1] ⁺ .

7- (1- (9H-purine-6-ylamino) ethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1)
7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (1j) (0.02 g, 0.08 mmol) in IPA (2 mL) , A mixture of commercially available 6-chloro-9H-purine (0.015 g, 0.1 mmol) and DIEA (0.065 g, 0.5 mmol) was stirred at 100 ° C. for 24 hours in a sealed tube. The mixture was r. t. It was cooled to and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (20: 1) and labeled Compound 7- (1- (9H-purin-6-ylamino) ethyl) -3-methyl-6-phenyl-. 5H-thiazolo [3,2-a] pyridine-5-one (1) was given. MS-ESI (m / z): 403 [M + 1] ⁺ .

７−（１−ヒドロキシアリル）−３−メチル−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２ａ）
表記化合物７−（１−ヒドロキシアリル）−３−メチル−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２ａ）を、臭化メチルマグネシウムを臭化ビニルマグネシウムで置き換えることにより、１ｈについて記載されたのと同じ手順を使用することで調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：２９８［Ｍ＋１］^＋。 Example 2
7- (1- (9H-purine-6-ylamino) propyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (2)

7- (1-Hydroxyallyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (2a)
Notation Compound 7- (1-Hydroxyallyl) -3-methyl-6-Phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (2a) is replaced with methylmagnesium bromide with vinylmagnesium bromide. Thereby, it was prepared by using the same procedure described for 1h. MS-ESI (m / z): 298 [M + 1] ⁺ .

7- (1-Hydroxypropyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (2b)
7- (1-Hydroxyallyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (2a) (0.033 g, 0.11 mmol) in EtOH (2 mL) , Pd / C (10%, 0.015 g), and cyclohexa-1,4-diene (0.08 g, 1 mmol) were stirred at 65 ° C. for 48 hours. The mixture was r. t. It was cooled to and filtered through Celite. The filtrate is concentrated and purified by preparative TLC eluting with PE / EA (1: 1), and the notation compound 7- (1-hydroxypropyl) -3-methyl-6-phenyl-5H-thiazolo [3, 2-a] Pyridine-5-one (2b) was given. MS-ESI (m / z): 300 [M + 1] ⁺ .

1- (3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) propyl methanesulfonate (2c)
Notation Compound 1- (3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) propylmethanesulfonate (2c), 7- (1-hydroxyethyl) -3-Methyl-6-Phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1h) 7- (1-hydroxypropyl) -3-methyl-6-phenyl-5H-thiazolo [3 , 2-a] Prepared by using the same procedure described for 1i by substituting with pyridine-5-one (2b). MS-ESI (m / z): 378 [M + 1] ⁺ .

7- (1-aminopropyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (2d)
Notation Compound 7- (1-aminopropyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (2d), 1- (3-methyl-5-oxo- 6-Phenyl-5H-thiazolo [3,2-a] Pyridine-7-yl) ethyl methanesulfonate (1i) 1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2] -A] Prepared by using the same procedure as described for 1j by substituting with pyridine-7-yl) propyl methanesulfonate (2c). MS-ESI (m / z): 299 [M + 1] ⁺ .

7- (1- (9H-purine-6-ylamino) propyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (2)
7- (1-Aminopropyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (2d) in t-BuOH (1 mL) (0.015 g, 0. A mixture of 05 mmol), commercially available 6-chloro-9H-purine (0.01 g, 0.06 mmol), and DIEA (0.065 g, 0.5 mmol) was stirred at 80 ° C. for 48 hours. The mixture was r. t. It was cooled to and concentrated. The residue was purified by preparative TLC eluting with DCM / MeOH (10: 1) and labeled Compound 7- (1- (9H-purin-6-ylamino) propyl) -3-methyl-6-phenyl- 5H-thiazolo [3,2-a] pyridine-5-one (2) was given. MS-ESI (m / z): 417 [M + 1] ⁺ .

ジメチル ２−（ピリジン−２−イルメチレン）スクシナート（３ａ）
表記化合物ジメチル ２−（ピリジン−２−イルメチレン）スクシナート（３ａ）を、４−メチルチアゾール−２−カルバルデヒド（１ａ）をピコリンアルデヒドで置き換えることにより、１ｃについて記載されたのと同じ手順を使用することで調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：２３６［Ｍ＋１］^＋。 Example 3
2- (1- (9H-Prin-6-ylamino) ethyl) -3-phenyl-4H-quinolizidine-4-one (3)

Dimethyl 2- (pyridin-2-ylmethylene) succinate (3a)
The same procedure as described for 1c is used by substituting the notation compound dimethyl 2- (pyridin-2-ylmethylene) succinate (3a) with picolinaldehyde for 4-methylthiazole-2-carbaldehyde (1a). Prepared by MS-ESI (m / z): 236 [M + 1] ⁺ .

Methyl 4-oxo-4H-quinolizidine-2-carboxylate (3b)
A mixture of dimethyl 2- (pyridin-2-ylmethylene) succinate (3a) (2.35 g, 10 mmol) and PTSa (0.2 g) in toluene (25 mL) was stirred at 110 ° C. for 7 hours. The reaction mixture was added to r. t. It was cooled to and concentrated. The residue was diluted with DCM (100 mL), washed with saturated aqueous NaHCO ₃ solution (50 mL), brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was recrystallized from PE / EtOAc to give the notation compound methyl 4-oxo-4H-quinolizidine-2-carboxylate (3b). MS-ESI (m / z): 204 [M + 1] ⁺ .

Methyl 3-iodo-4-oxo-4H-quinolizidine-2-carboxylate (3c)
Notation Compound Methyl 3-iodo-4-oxo-4H-quinolizidine-2-carboxylate (3c), methyl 3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-carboxylate (32-a) It was prepared by substituting 1d) with 4-oxo-4H-quinolizidine-2-carboxylate (3b) using the same procedure described for 1e. MS-ESI (m / z): 330 [M + 1] ⁺ .

Methyl 4-oxo-3-phenyl-4H-quinolizidine-2-carboxylate (3d)
Notation Compound Methyl 4-oxo-3-phenyl-4H-quinolidine-2-carboxylate (3d), methyl 6-iodo-3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7 It was prepared by replacing −carboxylate (1e) with methyl 3-iodo-4-oxo-4H-quinolidine-2-carboxylate (3c) using the same procedure described for 1f. MS-ESI (m / z): 280 [M + 1] ⁺ .

2- (Hydroxymethyl) -3-phenyl-4H-quinolizidine-4-one (3e)
CaCl ₂ (0.10 g, 0.9 mmol) in a solution of methyl 4-oxo-3-phenyl-4H-quinolidine-2-carboxylate (3d) (0.20 g, 0.71 mmol) in THF (15 mL). , Subsequently, NaBH ₄ (0.60 g, 15 mmol) was added. The mixture was stirred at 70 ° C. for 3.5 hours and the reaction was stopped at 0 ° C. with ice water (20 mL). The mixture was extracted with EtOAc (2 x 50 mL) and the extract was washed with brine (50 mL) and dried over Na ₂ SO ₄ . Filtration, concentration and residue purified by silica gel column chromatography eluting with PE / EtOAc (1: 1), labeled compound 2- (hydroxymethyl) -3-phenyl-4H-quinolidine-4- On (3e) was given. MS-ESI (m / z): 252 [M + 1] ⁺ .

4-Oxo-3-phenyl-4H-quinolizidine-2-carbaldehyde (3f)
A mixture of 2- (hydroxymethyl) -3-phenyl-4H-quinolizidine-4-one (3e) (0.10 g, 0.4 mmol) and MnO ₂ (1.9 g, 20 mmol) in dioxane (8 mL). The mixture was stirred at 90 ° C. for 2.5 hours. The mixture was filtered through Celite and the filtrate was concentrated to give a crude product of 4-oxo-3-phenyl-4H-quinolizidine-2-carbaldehyde (3f). The crude product was used directly in the next step. MS-ESI (m / z): 250 [M + 1] ⁺ .

2- (1-Hydroxyethyl) -3-phenyl-4H-quinolizidine-4-one (3 g)
Notation Compound 2- (1-Hydroxyethyl) -3-phenyl-4H-quinolidine-4-one (3 g), 3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine It was prepared by using the same procedure as described for 1h by replacing -7-carbaldehyde (1g) with 4-oxo-3-phenyl-4H-quinolidine-2-carbaldehyde (3f). MS-ESI (m / z): 266 [M + 1] ⁺ .

1- (4-oxo-3-phenyl-4H-quinolizidine-2-yl) ethyl methanesulfonate (3h)
Notation Compound 1- (4-oxo-3-phenyl-4H-quinolidine-2-yl) ethyl methanesulfonate (3h), 7- (1-hydroxyethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] 1i has been described by replacing pyridine-5-one (1h) with 2- (1-hydroxyethyl) -3-phenyl-4H-quinolidine-4-one (3g). Prepared by using the same procedure as. MS-ESI (m / z): 344 [M + 1] ⁺ .

2- (1-Aminoethyl) -3-phenyl-4H-quinolizidine-4-one (3i)
Notation Compound 2- (1-aminoethyl) -3-phenyl-4H-quinolidine-4-one (3i), 1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2- a] Description of 1j by substituting pyridine-7-yl) ethyl methanesulfonate (1i) with 1- (4-oxo-3-phenyl-4H-quinolidine-2-yl) ethyl methanesulfonate (3h). Prepared by using the same procedure as was done. MS-ESI (m / z): 265 [M + 1] ⁺ .

2- (1- (9H-Prin-6-ylamino) ethyl) -3-phenyl-4H-quinolizidine-4-one (3)
Notation Compound 2- (1- (9H-purin-6-ylamino) ethyl) -3-phenyl-4H-quinolidine-4-one (3), 7- (1-aminoethyl) -3-methyl-6- By replacing phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1j) with 2- (1-aminoethyl) -3-phenyl-4H-quinolidine-4-one (3i), 1 Prepared by using the same procedure described for. MS-ESI (m / z): 383 [M + 1] ⁺ .

２−（１−ヒドロキシプロピル）−３−フェニル−４Ｈ−キノリジン−４−オン（４ａ）
表記化合物２−（１−ヒドロキシプロピル）−３−フェニル−４Ｈ−キノリジン−４−オン（４ａ）を、臭化メチルマグネシウムを臭化エチルマグネシウムで置き換えることにより、３ｇについて記載されたのと同じ手順を使用することで調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：２８０［Ｍ＋１］^＋。 Example 4
2- (1- (9H-purine-6-ylamino) propyl) -3-phenyl-4H-quinolizidine-4-one (4)

2- (1-Hydroxypropyl) -3-phenyl-4H-quinolizidine-4-one (4a)
The same procedure as described for 3 g by replacing the notation compound 2- (1-hydroxypropyl) -3-phenyl-4H-quinolizidine-4-one (4a) with ethylmagnesium bromide. Was prepared by using. MS-ESI (m / z): 280 [M + 1] ⁺ .

1- (4-oxo-3-phenyl-4H-quinolizidine-2-yl) propyl methanesulfonate (4b)
Notation Compound 1- (4-oxo-3-phenyl-4H-quinolidine-2-yl) propyl methanesulfonate (4b), 7- (1-hydroxyethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] 1i has been described by replacing pyridine-5-one (1h) with 2- (1-hydroxypropyl) -3-phenyl-4H-quinolidine-4-one (4a). Prepared by using the same procedure as. MS-ESI (m / z): 358 [M + 1] ⁺ .

2- (1-Aminopropyl) -3-phenyl-4H-quinolizidine-4-one (4c)
Notation Compound 2- (1-aminopropyl) -3-phenyl-4H-quinolidine-4-one (4c), 1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2- a] Described for 1j by replacing pyridine-7-yl) ethyl methanesulfonate (1i) with 1- (4-oxo-3-phenyl-4H-quinolidine-2-yl) propyl methanesulfonate (4b). Prepared by using the same procedure as was done. MS-ESI (m / z): 378 [M + 1] ⁺ .

2- (1- (9H-purine-6-ylamino) propyl) -3-phenyl-4H-quinolizidine-4-one (4)
Notation Compound 2- (1- (9H-Prin-6-ylamino) propyl) -3-phenyl-4H-quinolidine-4-one (4), 7- (1-aminoethyl) -3-methyl-6- By replacing phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1j) with 2- (1-aminopropyl) -3-phenyl-4H-quinolidine-4-one (4c), 1 Prepared by using the same procedure described for. MS-ESI (m / z): 397 [M + 1] ⁺ .

メチル ６−（４−フルオロフェニル）−３−メチル−５−オキソ−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−カルボキシラート（５ａ）
表記化合物メチル ６−（４−フルオロフェニル）−３−メチル−５−オキソ−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−カルボキシラート（５ａ）を、フェニルボロン酸を（４−フルオロフェニル）ボロン酸で置き換えることにより、１ｆの合成法に従って調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：３１８［Ｍ＋１］^＋。 Example 5
7-(1-((9H-Prin-6-yl) amino) ethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (5) )

Methyl 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carboxylate (5a)
Notation compound Methyl 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carboxylate (5a), phenylboronic acid (4-fluorophenyl) ) Prepared according to the synthetic method of 1f by replacing with phenylboronic acid. MS-ESI (m / z): 318 [M + 1] ⁺ .

6- (4-Fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (5b)
Notation Compound 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (5b), methyl 3-methyl-5-oxo-6 -Phenyl-5H-thiazolo [3,2-a] Pyridine-7-carboxylate (1f) is methyl 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] ] Prepared according to 1 g synthetic method by substituting with pyridine-7-carboxylate (5a). MS-ESI (m / z): 288 [M + 1] ⁺ .

1-(6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl methanesulfonate (5c)
Notation Compound 1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl methanesulfonate (5c), 3-methyl -5-oxo-6-phenyl-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (1g) 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [ 3,2-a] Prepared according to the synthetic method of 1i by substituting with pyridine-7-carbaldehyde (5b). MS-ESI (m / z): 382 [M + 1] ⁺ .

7- (1-azidoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (5d)
1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl methanesulfonate (5c) in DMF (3 mL) ( A mixture of 0.266 g, 0.7 mmol) and NaN ₃ (0.13 g, 2.1 mmol) was stirred at 30 ° C. overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The organic phase was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to 7- (1-azidoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3]. , 2-a] A crude product of pyridine-5-one (5d) was given. The crude product was used directly in the next step. MS-ESI (m / z): 329 [M + 1] ⁺ .

7- (1-aminoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (5e)
7- (1-azidoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one in THF (5 mL) and water (0.13 g) A solution of 5d) (0.24 g, 0.73 mmol) and PPh ₃ (0.57 g, 2.2 mmol) was stirred at 40 ° C. overnight, concentrated, and the residue was purified to 7- (1- (1-). Aminoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one (5e) was given. MS-ESI (m / z): 303 [M + 1] ⁺ .

(2R) -N- (1- (1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl) -2-methoxy- 2-Phenylacetamide (5f)
(R) -2-methoxy-2-phenylacetic acid (0.15 g, 0.9 mmol), EDCI (0.24 g, 1.2 mmol), HOBT (0.1 g, 0.9 mmol) in DMF (6 mL), And a mixture of DIPEA (0.36 g, 3.0 mmol), r. t. 7- (1-aminoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] in THF (1.0 mL). A solution of pyridine-5-one (5e) (0.18 g, 0.6 mmol) was added. This solution was added to r. The mixture was stirred at t for 2 hours, diluted with water (50 mL), and extracted with EA (50 mL × 2). The organic phase was washed with 10% citric acid (20 mL), ₃ aqueous NaHCO solution (20 mL), and brine (20 mL), dried, concentrated, purified with TLC (PE: THF = 2: 1) and purified (PE: THF = 2: 1). 2R) -N- (1- (1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl) -2-methoxy-2 -Phenylacetamide (5fa and 5f-b) was given. MS-ESI (m / z): 451 [M + 1] ⁺ .

7- (1-aminoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridine-5-one (5 g)
A solution of 5fa (0.065 g, 0.144 mmol) in 8N HCl (6 mL) was stirred at 100 ° C. for 4 hours, followed by r. t. It was cooled to water, diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The aqueous layer was adjusted to pH = 11-12 with 2N NaOH and extracted at DCM: IPA = 4: 1 (3 x 30 mL). The organic phase was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated to 7- (1-aminoethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [ 3,2-a] Pyridine-5-one (5 g) was given and used directly in the next step. MS-ESI (m / z): 303 [M + 1] ⁺ .

7-(1-((9H-Prin-6-yl) amino) ethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (5) )
Notation Compound 7- (1-((9H-purin-6-yl) amino) ethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (5), 7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (1j), 7- (1-aminoethyl)- It was prepared according to the synthetic method of 1 by substituting with 6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridine-5-one (5 g). MS-ESI (m / z): 421 [M + 1] ⁺ .

６−（４−フルオロフェニル）−７−（１−ヒドロキシプロピル）−３−メチル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（６ａ）
表記化合物６−（４−フルオロフェニル）−７−（１−ヒドロキシプロピル）−３−メチル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（６ａ）を、３−メチル−５−オキソ−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−カルバルデヒド（１ｇ）を６−（４−フルオロフェニル）−３−メチル−５−オキソ−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−カルバルデヒド（５ｂ）で置き換えることにより、２ｂの合成法に従って調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：３１６［Ｍ＋１］^＋。 Example 6
7-(1-((9H-purin-6-yl) amino) propyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one (6) )

6- (4-fluorophenyl) -7- (1-hydroxypropyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (6a)
Notation Compound 6- (4-fluorophenyl) -7- (1-hydroxypropyl) -3-methyl-5H-thiazolo [3,2-a] Pyridine-5-one (6a), 3-methyl-5- Oxo-6-phenyl-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (1 g) 6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2] -A] Prepared according to the synthetic method of 2b by substituting with pyridine-7-carbaldehyde (5b). MS-ESI (m / z): 316 [M + 1] ⁺ .

1-(6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) propyl methanesulfonate (6b)
Notation Compound 1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) propyl methanesulfonate (6b), 7- ( 1-Hydroxyallyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (2a) 6- (4-fluorophenyl) -7- (1-hydroxypropyl) It was prepared according to the synthetic method of 2c by substituting -3-methyl-5H-thiazolo [3,2-a] pyridine-5-one (6a). MS-ESI (m / z): 396 [M + 1] ⁺ .

7-(1-((9H-purin-6-yl) amino) propyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one (6) )
Notation Compound 7- (1-((9H-purin-6-yl) amino) propyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridine-5-one (6), 1- (6- (4-fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl methanesulfonate (5c) 1 -(6- (4-Fluorophenyl) -3-methyl-5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) propyl Methanesulfonate (6b) to synthesize 5 Prepared according to the method. MS-ESI (m / z): 435 [M + 1] ⁺ .

Following essentially the same procedure as described for Example 5, Examples 7-11 listed in Table 1 are either commercially available or commercially available starting with the appropriately substituted thiazole. Prepared using any suitable Grignard reagent readily available by methods known in.

（４−クロロチアゾール−２−イル）メタノール（１２ａ）
（４−クロロチアゾール−２−イル）メタノール（１２ａ）を、国際公開公報第２０１３１４９３６２号に記載された方法に従って調製した。 Example 12
7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] Pyridine-5-one (12) )

(4-Chlorothiazole-2-yl) Methanol (12a)
(4-Chlorothiazole-2-yl) methanol (12a) was prepared according to the method described in WO 2013149362.

4-Chlorothiazole-2-carbaldehyde (12b)
DMP (6.04 g, 14.25 mol) in a solution of (4-chlorothiazole-2-yl) methanol (12a) (1.93 g, 12.95 mmol) in DCM (20 mL) at 0-5 ° C. In addition, the mixture was stirred at the same temperature for 2-4 hours, diluted with DCM (50 mL), washed with saturated aqueous NaHCO ₃ solution (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with PE / EtOAc (20: 1) to give 4-chlorothiazole-2-carbaldehyde (12b). MS-ESI (m / z): 148, 150 [M + 1] ⁺ .

3-Chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (12c)
Notation Compound 3-Chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] Pyridine-7-carbaldehyde (12c), 4-methylthiazole-2-carbaldehyde (12c) It was prepared according to the synthetic method of 1 g by substituting 1a) with 4-chlorothiazole-2-carbaldehyde (12b). MS-ESI (m / z): 308, 310 [M + 1] ⁺ .

(E) -N-((3-Chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) methylene) -2-methylpropane-2 -Sulfinamide (12d)
3-Chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridin-7-carbaldehyde (12c) in DCM (80 mL) (3.0 g, 10.0 mmol) ), (S) -tert-butanesulfinamide (1.815 g, 15.0 mmol), and Cs ₂ CO ₃ (9.61 g, 30.0 mol). t. Was stirred for 2 hours. The mixture was washed with water (80 mL) and the organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (3: 1) and (E) -N-((3-chloro-6- (3-fluorophenyl) -5-oxo-5H). -Thiazolo [3,2-a] pyridin-7-yl) methylene) -2-methylpropan-2-sulfinamide (12d) was given. MS-ESI (m / z): 411, 413 [M + 1] ⁺ .

N- (1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl) -2-methylpropan-2-sulfin Amide (12e)
(E) -N- in THF (80 mL) ((3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) methylene)- Methylmagnesium chloride (20.0 mL, 46.5 mmol) was added dropwise to a solution of 2-methylpropan-2-sulfinamide (12d) (3.1 g, 7.54 mmol) at −78 ° C. The mixture was stirred at the same temperature for 1.5 hours and water was added. The mixture was extracted with EA (2 x 100 mL). The organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / DCM (1: 1) and N- (1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo). [3,2-a] Pyridine-7-yl) ethyl) -2-methylpropan-2-sulfinamide (12e) was given. MS-ESI (m / z): 427, 249 [M + 1] ⁺ .

7- (1-aminoethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] Pyridine-5-one (12f)
N- (1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridin-7-yl) ethyl) -2- in EtOH (20 mL) In a solution of methylpropane-2-sulfinamide (12e) (1.65 g, 3.8 mmol), concentrated HCl (5.0 mL) was added to r. t. And the mixture was stirred for 0.5 hours. The mixture was quenched with NH ₄ OH (50 mL) and extracted with DCM (2 x 100 mL). The organic phase was washed with brine, dried over Na ₂ SO ₄ , concentrated and 7- (1-aminoethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2]. -A] A crude product of pyridine-5-one (12f) was given. The crude product was used directly in the next step. MS-ESI (m / z): 323, 325 [M + 1] ⁺ .

6-Chloro-9- (Tetrahydro-2H-Pyran-2-yl) -9H-Purine (12g)
6-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (12 g) was prepared according to the method described in WO 2008153947.

3-Chloro-6- (3-fluorophenyl) -7-(1-((9- (tetrahydro-2H-pyran-2-yl) -9H-purine-6-yl) amino) ethyl) -5H-thiazolo [3,2-a] Pyridine-5-on (12h)
6-Chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (12 g) (0.75 g, 3.1 mmol), TBAF (6 mL), and 4AMs (0) in DMSO (6 mL). a mixture of .5G), at 30 ° C., stirred for 2 hours under _{N 2} atmosphere, then 7- (1-aminoethyl) -3-chloro-6- (3-fluorophenyl) -5H- thiazolo [3 , 2-a] Pyridine-5-one (12f) (0.3 g, 1.0 mmol) was added. The mixture was r. t. Stir for 5 hours, filter through Celite, dilute with 50 mL of water and extract with EtOAc (2 x 50 mL). The organic phase was washed with brine (50 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1: 1) to 3-chloro-6- (3-fluorophenyl) -7- (1-((9- (tetrahydro-2H)). −Pyran-2-yl) -9H-purine-6-yl) amino) ethyl) -5H-thiazolo [3,2-a] pyridine-5-one (12h) was given. MS-ESI (m / z): 525, 527 [M + 1] ⁺ .

7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] Pyridine-5-one (12) )
3-Chloro-6- (3-fluorophenyl) -7-(1-((9- (tetrahydro-2H-pyran-2-yl) -9H-purine-6) in EtOH (15 mL) / DCM (50 mL)) In a solution of −yl) amino) ethyl) -5H-thiazolo [3,2-a] pyridine-5-one (12h) (1.33 g, 2.5 mmol), 6N HCl (5.0 mL) was added to r. t. Add in and add the mixture to r. t. Was stirred for 1.0 hour. The mixture was quenched with NH ₄ OH (100 mL), extracted with DCM (2 x 100 mL) and the organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated. The residue was purified by recrystallization with EtOAc and 7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6- (3-fluorophenyl) -5H- Thiazolo [3,2-a] pyridine-5-one (12) was given. MS-ESI (m / z): 441, 443 [M + 1] ⁺ .

Following essentially the same procedure as described for Example 12, Examples 13-19 listed in Table 2 are either commercially available or commercially available starting with the appropriately substituted thiazole. Prepared using any suitable Grignard reagent readily available by methods known in.

表記化合物７−（（（９Ｈ−プリン−６−イル）アミノ）（シクロプロピル）メチル）−３−クロロ−６−（３−フルオロフェニル）−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２０）を、（Ｓ）−tert−ブタンスルフィンアミドを（Ｒ）−tert−ブタンスルフィンアミドで置き換え、臭化メチルマグネシウムを臭化シクロプロピルマグネシウムで置き換えることにより、１２の合成法に従って調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：４６７、４６９［Ｍ＋１］^＋。 Example 20
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one (20)

Notation Compound 7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridine-5 Prepared according to 12 synthetic methods by substituting -on (20) with (S) -tert-butanesulfinamide with (R) -tert-butansulfinamide and methylmagnesium bromide with cyclopropylmagtanium bromide did. MS-ESI (m / z): 467, 469 [M + 1] ⁺ .

Following essentially the same procedure as described for Example 20, Examples 21-23 listed in Table 3 are either commercially available or commercially available starting with the appropriately substituted thiazole. Prepared using any suitable boronic acid readily available by known methods in.

２−メチル−Ｎ−（（３−メチル−５−オキソ−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−イル）メチレン）プロパン−２−スルフィンアミド（２４ａ）
ＤＣＭ（２５mL）中の３−メチル−５−オキソ−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−カルバルデヒド（１ｇ）（０．１５ｇ、０．５５６mmol）、（Ｒ）−tert−ブタンスルフィンアミド（０．１８ｇ、１．４８８mmol）、及びＣｓ_２ＣＯ_３（０．５４ｇ、１．６５７mol）の混合物を、４０℃で一晩撹拌した。混合物を、水（２５mL）で洗浄し、有機相を、ブライン（２０mL）で洗浄し、Ｎａ_２ＳＯ_４で乾燥させ、濃縮して、２−メチル−Ｎ−（（３−メチル−５−オキソ−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−イル）メチレン）プロパン−２−スルフィンアミド（２４ａ）の粗生成物を与えた。同粗生成物を、次の工程に直接使用した。ＭＳ−ＥＳＩ（ｍ／ｚ）：３７３［Ｍ＋１］^＋。 Example 24
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (24)

2-Methyl-N-((3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) methylene) Propane-2-sulfinamide (24a)
3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-carbaldehyde (1 g) (0.15 g, 0.556 mmol) in DCM (25 mL), (R) A mixture of -tert-butanesulfinamide (0.18 g, 1.488 mmol) and Cs ₂ CO ₃ (0.54 g, 1.657 mol) was stirred at 40 ° C. overnight. The mixture was washed with water (25 mL) and the organic phase was washed with brine (20 mL), dried with Na ₂ SO ₄ and concentrated to 2-methyl-N-((3-methyl-5-oxo). A crude product of -6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) methylene) propan-2-sulfinamide (24a) was given. The crude product was used directly in the next step. MS-ESI (m / z): 373 [M + 1] ⁺ .

N- (Cyclopropyl (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) methyl) -2-methylpropan-2-sulfinamide (24b)
2-Methyl-N- ((3-Methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridin-7-yl) methylene) propan-2-sulfinamide in THF (15 mL) Cyclopropyl magnesium bromide (5.0 mL, 5.0 mmol) was added dropwise to the solution of (24a) (0.207 g, 0.555 mmol) at −78 ° C. and the mixture was stirred at the same temperature for 2 hours. The reaction was stopped with water and the mixture was extracted with EtOAc (2 x 25 mL). The organic phase was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel column chromatography eluting with EtOAc: PE (2: 1) and N- (cyclopropyl (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-)]. a] Pyridin-7-yl) methyl) -2-methylpropan-2-sulfinamide (24b) was given. MS-ESI (m / z): 415 [M + 1] ⁺ .

7- (Amino (cyclopropyl) methyl) -3-methyl-6-Phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (24c)
Notation Compound 7- (amino (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (24c), N- (1- (3-chloro) -6- (3-Fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) -2-methylpropan-2-sulfinamide (12e) N- (cyclo) By replacing with propyl (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) methyl) -2-methylpropan-2-sulfinamide (24b). It was prepared according to the synthetic method of 12f. MS-ESI (m / z): 311 [M + 1] ⁺ .

7- (Cyclopropyl ((9- (tetrahydro-2H-pyran-2-yl) -9H-purine-6-yl) amino) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2- a] Pyridine-5-on (24d)
7- (Amino (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (24c) in IPA (5 mL) (0.062 g, 0. 2 mmol), 6-chloro-9- (tetrahydro-2H-pyran-2-yl) -9H-purine (12 g) (0.057 g, 0.24 mmol), and DIPEA (0.103 g, 0.8 mmol) mixture Was stirred at 80 ° C. overnight. The mixture was r. t. The solvent was evaporated. The residue was purified by silica gel column chromatography eluting with EtOAc and 7- (cyclopropyl ((9- (tetrahydro-2H-pyran-2-yl) -9H-purine-6-yl) amino) methyl). -3-Methyl-6-phenyl-5H-thiazolo [3,2-a] pyridine-5-one (24d) was given. MS-ESI (m / z): 513 [M + 1] ⁺ .

7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (24)
Notation Compound 7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (24) 3-Chloro-6- (3-fluorophenyl) -7-(1-((9- (tetrahydro-2H-pyridine-2-yl) -9H-purine-6-yl) amino) ethyl) -5H -Thiazolo [3,2-a] Pyridine-5-one (12h) 7- (cyclopropyl ((9- (tetrahydro-2H-pyran-2-yl) -9H-purine-6-yl) amino) methyl ) -3-Methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (24d) was used to prepare according to 12 synthetic methods. MS-ESI (m / z): 429 [M + 1] ⁺ .

表記化合物７−（（（９Ｈ−プリン−６−イル）アミノ）（シクロプロピル）メチル）−６−（３−フルオロフェニル）−３−メチル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２５）を、Ｓｕｚｕｋｉカップリング工程において、（３−フルオロフェニル）ボロン酸を使用することにより、２４の合成法に従って調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：４４７［Ｍ＋１］^＋。 Example 25
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one (25)

Notation Compound 7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridine-5 -On (25) was prepared according to 24 synthetic methods by using (3-fluorophenyl) boronic acid in the Suzuki coupling step. MS-ESI (m / z): 447 [M + 1] ⁺ .

７−（１−アミノエチル）−３−メチル−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２６ａ）
表記化合物７−（１−アミノエチル）−３−メチル−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（２６ａ）を、１−（６−（４−フルオロフェニル）−３−メチル−５−オキソ−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−イル）エチル メタンスルホナート（５ｃ）を１−（３−メチル−５−オキソ−６−フェニル−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−イル）エチル メタンスルホナート（１ｉ）で置き換えることにより、５ｇの合成法に従って調製した。ＭＳ−ＥＳＩ（ｍ／ｚ）：２８５［Ｍ＋１］^＋。 Example 26
2-Amino-4-methyl-6-((1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) pyrimidine-5 -Carbonitrile (26)

7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (26a)
Notation Compound 7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] Pyridine-5-one (26a), 1- (6- (4-fluorophenyl) -3-Methyl-5-oxo-5H-thiazolo [3,2-a] Pyridine-7-yl) Ethyl methanesulfonate (5c) 1- (3-Methyl-5-oxo-6-phenyl-5H- It was prepared according to the synthetic method of 5 g by substituting with thiazolo [3,2-a] pyridine-7-yl) ethyl methanesulfonate (1i). MS-ESI (m / z): 285 [M + 1] ⁺ .

2-Amino-4-methyl-6-((1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) pyrimidine-5 -Carbonitrile (26)
7- (1-aminoethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one (26a) in CH ₃ CN (1 mL) (0.05 g, 0. 177 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.0357 g, 0.211 mmol), and DIPEA (0.0795 g, 0.62 mmol) at 80 ° C. overnight. It was heated. The mixture was r. t. It was cooled to water, diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The extract was dried over Na ₂ SO ₄ and the solvent was evaporated. The residue was purified by recrystallization with EtOAc to 2-amino-4-methyl-6-((1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-). a] Pyridine-7-yl) ethyl) amino) pyrimidine-5-carbonitrile (26) was given. MS-ESI (m / z): 417 [M + 1] ⁺ .

ＤＭＳＯ（１mL）中の７−（１−アミノエチル）−３−クロロ−６−（３−フルオロフェニル）−５Ｈ−チアゾロ［３，２−ａ］ピリジン−５−オン（１２ｆ）（０．０１５ｇ、０．０５mmol）、２−アミノ−４−クロロ−６−メチルピリミジン−５−カルボニトリル（０．０１７ｇ、０．１mmol）、及びＴＥＡ（０．０２ｇ、０．２mmol）の混合物を、８５℃で１．５時間加熱した。混合物を、ｒ．ｔ．に冷まし、水（２０mL）で希釈し、ＥｔＯＡｃ（２×２０mL）で抽出した。抽出物を、Ｎａ_２ＳＯ_４で乾燥させた。溶媒を蒸発させた。残留物を、ＥｔＯＡｃ／ＤＣＭ（１：２）により溶出するシリカゲル クロマトグラフィーにより精製して、２−アミノ−４−（（１−（３−クロロ−６−（３−フルオロフェニル）−５−オキソ−５Ｈ−チアゾロ［３，２−ａ］ピリジン−７−イル）エチル）アミノ）−６−メチルピリミジン−５−カルボニトリル（２７）を与えた。ＭＳ−ＥＳＩ（ｍ／ｚ）：４５５、４５７［Ｍ＋１］^＋。 Example 27
2-Amino-4-((1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) -6 -Methylpyrimidine-5-Carbonitrile (27)

7- (1-aminoethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one (12f) (0.015 g) in DMSO (1 mL) , 0.05 mmol), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.017 g, 0.1 mmol), and TEA (0.02 g, 0.2 mmol) at 85 ° C. Was heated for 1.5 hours. The mixture was r. t. It was cooled to water, diluted with water (20 mL) and extracted with EtOAc (2 x 20 mL). The extract was dried over Na ₂ SO ₄ . The solvent was evaporated. The residue was purified by silica gel chromatography eluting with EtOAc / DCM (1: 2) to 2-amino-4-((1- (3-chloro-6- (3-fluorophenyl) -5-oxo). -5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) -6-methylpyrimidine-5-carbonitrile (27) was given. MS-ESI (m / z): 455, 457 [M + 1] ⁺ .

Cell Proliferation Assay A mechanism system assay using SU-DHL-6 cells (ATCC number: CRL-2959) was developed to investigate whether a compound can inhibit the activity of PI3K in cells. did. In this assay, inhibition of PI3K-δ was detected by inhibition of SU-DHL-6 cell proliferation. SU-DHL-6 cells were cultured in culture flasks to 40-80% confluent in RPMI-1640 supplemented with 10% fetal bovine serum. Cells were collected and seeded on 96-well plates at 30,000 cells / well. The plates were incubated overnight at 37 ° C. and 5% CO ₂ to bind. The compound was added to the plate. The final concentrations of the compounds were 10000, 3333.3, 1111.1, 270.4, 123.5, 41.2, 13.7, 4.6, and 1.5 nM. The plate was placed at 37 ° C. and 5% CO ₂ for 48 hours. After removing the medium, a mixture of 20 μl MTS / 100 μl medium was added to each well and the plates were incubated for exactly 2 hours. The reaction was stopped by adding 25 μl of 10% SDS per well. Absorbance at 490 nm and 650 nm (reference wavelength) was measured. IC _50s were calculated using GraphPad Prism 5.0.

The cancer cell line WSU-NHL (DSMZ number: ACC 58) was maintained in RPMI-1640 medium containing 10% FBS at 37 ° C. in an atmosphere of 5% CO ₂ . Tumor cells were routinely subcultured twice a week by trypsin-EDTA, and cells growing in the logarithmic growth phase were collected, counted, and placed in a 96-well plate at 5000 cells / well. Sown. After culturing for 24 hours, serially diluted test material was added to the wells, then the assay plate was returned to the incubator and culturing was continued for 48 hours. At the end of the incubation, assay plates were detected with the Promega CellTiter-Glo Luminescent Cell Survival Assay Kit (Promege 7572). Emission records for each well were read by a 2104 EnVision plate reader. The data was interpreted by GraphPad Prism 5 software.

The selected compounds prepared above were assayed according to the biological techniques described herein. The results are given in Table 5.

All references cited herein are incorporated by reference in their entirety.

Claims (24)

Equation (I):

[During the ceremony,
AB is as follows:

5-6 member condensed pyridone ring system
W is selected from aryl and heteroaryl, where aryl and heteroaryl are unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 ~, respectively. 10} Cycloalkyl, C _3-10 Cycloalkyl-C _1-4 Alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , Halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , ( CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl- It is substituted with at least one substituent independently selected from C _1-4 alkyl.
R ¹ is hydrogen, halogen, cyano, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, Heterocyclyl-C _1-4 alkyl, aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl are selected, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are respectively. , C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C ( O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ) , CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ independently It is substituted with at least one substituent of choice, where the aryl and heteroaryl are unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, respectively. C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCON R ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) ) _T NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹⁾ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) ) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and It is substituted with at least one substituent independently selected from heteroaryl-C _1-4 alkyl.
R ² is hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C ₁ Selected from _{~ 4alkyl} , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted. Or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S ( O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , At least selected independently of CF ₃ , OCHF ₂ , and OCF ₃ Is also substituted with one substituent, where the aryl and heteroaryl are unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _{3 ~, respectively. 10} Cycloalkyl, C _3-10 Cycloalkyl-C _1-4 Alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , Halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , ( CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl- It is substituted with at least one substituent independently selected from C _1-4 alkyl.
R ³ is selected from hydrogen, C _1-10 alkyl, and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted or C _1-10 alkyl, C _{2-2, respectively. 10} alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) ) _R R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , ( CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR Select independently from ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF _3. Substituted with at least one substituent to be
R ⁴ is selected from hydrogen, halogen, _{cyano, C 1 to 10 alkyl, C 2 to 10 alkenyl, C 2 to 10 alkynyl, C 3 to 10} cycloalkyl, and _{C 3 to 10} cycloalkyl _{-C 1 to 4} alkyl Where the alkyl, alkenyl, alkynyl, and cycloalkyl are unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, respectively, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰⁾ ) _T SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) Substituted with at least one substituent independently selected from NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ .
R ⁵ are independently hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC ( O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF _{3 are} selected, where alkyl, alkenyl, alkynyl, and cycloalkyl are each unsubstituted or Alternatively, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹⁾ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹⁾ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) ) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) Substituted with at least one substituent independently selected from NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ .
Each R ⁷ and each R ⁸ contains hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, Aryl-C _1-4 Alk, Heteroaryl, and Heteroaryl-C _{1-4 Alk} , where alkyl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl are each unsubstituted. Are or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, NO ₂ , halogen, CN, Substituted with at least one substituent independently selected from CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ , aryl and heteroaryl are unsubstituted or C _1-10 alkyl, respectively. , C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, NO ₂ , halogen, CN, CHF ₂ , CF ₃ , OCHF ₂ , OCF _3. Aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl are substituted with at least one substituent independently selected, or R ⁷ and R ⁸ are Together with the atoms to which they are attached, they form a 4- to 12-membered heterocycle, which is selected independently of oxygen, sulfur, and nitrogen, 0, 1, or 2 additions. Heteroatomic or unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _{1- 4} alkyl, NO _2. 1 to, _{halogen, CN, CHF 2, CF 3} , OCHF 2, OCF 3, aryl, _{-C 1 to 4} alkyl, selected heteroaryl, and heteroaryl _{-C 1 to 4} alkyl Substituted with two groups,
Each R ⁹ and each R ¹⁰ are hydrogen, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, cycloalkyl, cycloalkyl-C _1-4 alkyl, heterocyclyl, heterocyclyl-C _1-4 alkyl. , Aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl, or R ⁹ and R ¹⁰ together with the carbon atom to which they are attached. It forms a 3- to 7-membered ring, which contains 0, 1, or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is unsubstituted or unsubstituted. Alternatively, C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , Halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CH ₂ ) _t OR ⁸ , (CH (C _1-10 alkyl)) _t OR ⁸ , (C (C _1-10 alkyl) ₂ ) _t OR ⁸ , (CH ₂ ) _t NR ⁷ R ⁸ , (CH (CH) C _1-10 alkyl)) _t NR ⁷ R ⁸ , (C (C _1-10 alkyl) ₂ ) _t NR ⁷ R ⁸ , (CH ₂ ) _t SR ⁸ , (CH (C _1-10 alkyl)) _t SR ⁸ , (C (C _1-10 alkyl) ₂ ) _t SR ⁸ , (CH ₂ ) _t S (O) _r R ⁸ , (CH (C _1-10 alkyl)) _t S (O) _r R ⁸ , ( C (C _1-10 alkyl) ₂ ) _t S (O) _r R ⁸ , (CH ₂ ) _t CO ₂ R ⁸ , (CH (C _1-10 alkyl)) _t CO ₂ R ⁸ , (C (C _{1) 10} alkyl) ₂ ) _t CO ₂ R ⁸ , (CH ₂ ) _t CONR ⁷ R ⁸ , (CH (C _1-10 alkyl)) _t CONR ⁷ R ⁸ , (C (C _1-10 alkyl) ₂ ) _t CONR ⁷ R ⁸ , (CH ₂ ) _t NR ⁷ CO ₂ R ⁸ , (CH (C _1-10 alkyl)) _t NR ⁷ CO ₂ R ⁸ , (C (C _1-10 alkyl) ₂ ) _t NR ⁷ CO ₂ R ⁸ , (CH ₂ ) _t OCONR ⁷ R ⁸ , (CH (C _1-10 alkyl)) _t OCONR ⁷ R ⁸ , (C (C _1-10 alkyl) ₂ ) _t OCONR ⁷ R ⁸ , (CH ₂ ) _t NR ⁷ CONR ⁷ R ⁸ , (CH (C _1-10 alkyl)) _t NR ⁷ CONR ⁷ R ⁸ , (C (C _1-10 alkyl) ₂ ) _t NR ⁷ CONR ⁷ R ⁸ , (CH ₂ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , (CH (C _{1 to 10} alkyl)) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , (C (C _{1 to 10} alkyl) ₂ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CH ₂ ) _t NR ⁷ R ⁸ , O (CH (C _1-10 alkyl)) _t NR ⁷ R ⁸ , O (C (C _1-10 alkyl) ₂ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CH ₂ ) _t OR ⁸ , C (O) (CH (C _1-10 alkyl)) _t OR ⁸ , C (O) (C (C _1-10 alkyl) ₂ ) _t OR ⁸ , C (O) (CH ₂ ) _t NR ⁷ R ⁸ , C (O) (CH (C _1-10 alkyl)) _t NR ⁷ R ⁸ , C (O) (C (C _1-10 alkyl) ₂ ) _T NR ⁷ R ⁸ , C (O) (CH ₂ ) _t SR ⁸ , C (O) (CH (C _1-10 alkyl)) _t SR ⁸ , C (O) (C (C _1-10 alkyl)) ₂ ) _t SR ⁸ , C (O) (CH ₂ ) _t S (O) _r R ⁸ , C (O) (CH (C _1-10 alkyl)) _t S (O) _r R ⁸ , C (O) (C (C _1-10 alkyl) ₂ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CH ₂ ) _t CONR ⁷ R ⁸ , CO ₂ (CH (C _1-10 alkyl)) _t CONR ⁷ R ⁸ , CO ₂ (C (C _1-10 alkyl) ₂ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF 1 selected from ₃ Substituted with ~ 2 groups,
m is independently selected from 0, 1及Beauty 2,
Each r is independently selected from 1 and 2
Each t is selected independently of 1, 2, and 3]
The compound indicated by, or a pharmaceutically acceptable salt thereof. AB is

The compound according to claim 1, or a pharmaceutically acceptable salt thereof. R ⁵ is selected from hydrogen, halogen, CF ₃ , C _1-10 alkyl, and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted or C _1-10 , respectively. Alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , Halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) ) _T OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF ₃ The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is substituted with at least one substituent independently selected from the above. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen, halogen, C _1-6 alkyl, CF ₃ , and cyclopropyl. The compound according to claim 4, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from hydrogen, chloro, methyl, ethyl, CF ₃ , and cyclopropyl. The compound according to claim 5, wherein R ⁵ is selected from chloro, methyl, and CF ₃ , or a pharmaceutically acceptable salt thereof. R ¹ is aryl, where aryl is unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3 ~. 10} Cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR) ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) Independent of NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which is substituted with at least one substituent selected therein. R ¹ is phenyl, where phenyl is unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3 ~. 10} Cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR) ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) ) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) Independent of NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl The compound according to claim 7, or a pharmaceutically acceptable salt thereof, which is substituted with at least one substituent selected therein. The compound according to claim 8, wherein R ¹ is phenyl, wherein the phenyl is unsubstituted or substituted with at least one substituent selected independently of halogen, or the like. A pharmaceutically acceptable salt. Salts R ¹ is phenyl, where the phenyl is unsubstituted or substituted by fluoro in is substituted, the compound according to claim 9, or their pharmaceutically acceptable. R ² is selected from C _1-10 alkyl and C _3-10 cycloalkyl, where the alkyl and cycloalkyl are unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C. _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10 cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰⁾ ) _T NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCNR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R) ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , At least one selected independently of NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , and OCF _3. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, which is substituted with one substituent. Salts R ² is methyl, ethyl, isopropyl, and is selected from cyclopropyl, compound of claim 11 wherein, the or their pharmaceutically acceptable. W is heteroaryl, where heteroaryl is unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _{3 -10} Cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS ( O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O ( CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C ( O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC (O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) ) From NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl The compound according to any one of claims 1 to 12, which is substituted with at least one independently selected substituent, or a pharmaceutically acceptable salt thereof. W is

The compound according to claim 13, or a pharmaceutically acceptable salt thereof. W is pyrimidine, where pyrimidine is unsubstituted or C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _3-10 cycloalkyl, C _3-10. Cycloalkyl-C _1-4 alkyl, OR ⁸ , NR ⁷ S (O) _r R ⁸ , NO ₂ , halogen, S (O) _r R ⁷ , SR ⁸ , S (O) ₂ OR ⁷ , OS (O) ₂ R ⁸ , S (O) _r NR ⁷ R ⁸ , NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t OR ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t SR ⁸ , (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , (CR ⁹ R ¹⁰ ) _t CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CO ₂ R ⁸ , (CR ⁹ R ¹⁰ ) _t OCONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ CONR ⁷ R ⁸ , (CR ⁹ R ¹⁰ ) _t NR ⁷ SO ₂ NR ⁷ R ⁸ , O (CR ⁹⁾ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) R ⁷ , C (O) (CR ⁹ R ¹⁰ ) _t OR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t NR ⁷ R ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t SR ⁸ , C (O) (CR ⁹ R ¹⁰ ) _t S (O) _r R ⁸ , CO ₂ R ⁸ , CO ₂ (CR ⁹ R ¹⁰ ) _t CONR ⁷ R ⁸ , OC ( O) R ⁷ , CN, C (O) NR ⁷ R ⁸ , NR ⁷ C (O) R ⁸ , OC (O) NR ⁷ R ⁸ , NR ⁷ C (O) OR ⁸ , NR ⁷ C (O) NR ⁷ R ⁸ , CR ⁷ (N-OR ⁸ ), CHF ₂ , CF ₃ , OCHF ₂ , OCF ₃ , aryl, aryl-C _1-4 alkyl, heteroaryl, and heteroaryl-C _1-4 alkyl independent The compound according to claim 13, or a pharmaceutically acceptable salt thereof, which is substituted with at least one substituent selected in the above. W is

The compound according to claim 15, or a pharmaceutically acceptable salt thereof. The compound according to any one of claims 1 to 16, wherein R ³ is hydrogen, or a pharmaceutically acceptable salt thereof. Salts R ⁴ is hydrogen, the compound of any one of claims 1 to 17, or their pharmaceutically acceptable. following:
7-(1-((9H-purin-6-yl) amino) ethyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (4-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (2-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-ethyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (2-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) ethyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-Prin-6-yl) amino) ethyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] Pyridine-5 -On,
7-(1-((9H-purin-6-yl) amino) propyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridine-5 -On,
7-(1-((9H-purin-6-yl) amino) ethyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(1-((9H-purin-6-yl) amino) propyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6- (3-fluorophenyl) -5H-thiazolo [3,2-a] pyridin-5-one ,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-chloro-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridine -5-on,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -6-phenyl-3- (trifluoromethyl) -5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-Prin-6-yl) amino) (cyclopropyl) methyl) -3-methyl-6-phenyl-5H-thiazolo [3,2-a] pyridin-5-one,
7-(((9H-purin-6-yl) amino) (cyclopropyl) methyl) -6- (3-fluorophenyl) -3-methyl-5H-thiazolo [3,2-a] pyridin-5-one ,
2-Amino-4-methyl-6-((1- (3-methyl-5-oxo-6-phenyl-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) pyrimidine-5 -Carbonitrile,
2-Amino-4-((1- (3-chloro-6- (3-fluorophenyl) -5-oxo-5H-thiazolo [3,2-a] pyridine-7-yl) ethyl) amino) -6 -A compound selected from methylpyrimidine-5-carbonitrile, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The pharmaceutical composition according to claim 20, wherein the phosphoinositide 3-kinase is modulated. 20. The pharmaceutical composition of claim 20, for treating, alleviating, or preventing a condition that responds to inhibition of phosphoinositide 3-kinase. The pharmaceutical composition according to claim 20, for treating a cell proliferative disorder. The pharmaceutical composition according to claim 22 or 23, further comprising a second therapeutic agent.